Modified release formulations containing drug-ion exchange resin complexes

ABSTRACT

A particulate, modified release barrier coated drug-cation exchange resin complex comprising a core composed of a drug complexed with a pharmaceutically acceptable ion-exchange resin is provided. Methods of making and products containing this coated complex are described.

BACKGROUND OF THE INVENTION

The present invention relates to pharmaceutical preparations having adrug-ion exchange resin complex that is treated to provide programmablerelease characteristics in the gastrointestinal tract.

One important aspect of drug therapy is the effect of a drug for anextended time and in many cases, the longer the time, the moresubstantial the benefit.

Use of ion-exchange resins to form a drug-ion exchange resin complex iswell known and is described, for example, in U.S. Pat. No. 2,990,332. Inthis patent, the use of an ion-exchange resin to form a complex withionic drugs and thereby delay the drug release from such complexes isdescribed. Such delay in drug release was deemed to be of relativelyshort duration. Since then there have been additional publications andpatents (e.g., U.S. Pat. Nos. 3,138,525; 3,499,960; 3,594,470; BelgianPatent No. 729,827; German Patent No. 2,246,037) that describe use ofsuch ion-exchange resin complexes with water-permeable diffusion barriercoatings of the drug-ion exchange resin complex coated to alter therelease of drugs from the drug-ion exchange resin complex.

Sustained or prolonged release dosage forms of various drugs are knownand commercially available. However, there are only a few productsavailable that provide sustained release of the drug from the very fineparticles of coated drug-ion exchange complexes. A recent US PublishedPatent Application No. US 2005/0181050 A1, published Aug. 18, 2005,mentions that few modified release liquids containing drug-loaded ionexchange resin particles are commercially available. It further statesthat such products require several time consuming steps and require theuse of a potentially hazardous step of coating from a solvent basedsolution. The regulatory authorities require that such solvents arethoroughly removed from the pharmaceutical products before ingestion.

Raghunathan in U.S. Pat. Nos. 4,221,778; 4,847,077 and Raghunathan etal. in J. Pharm. Sci., Vol 70, pp 379-384, April 1981, describe treatingdrug-ion exchange resin complexes with water soluble, hydrophilicimpregnating (solvating) agents such as polyethylene glycol and othersso as to enable the coating of drug-ion exchange resin complexes with awater-permeable diffusion barrier. These publications indicate that thedrug-ion exchange resin tended to swell when in contact with water,causing the coating layer to fracture and prematurely release the drugthereby adversely impacting the purpose of the coating (i.e., controlrelease). Attempts to minimize such rupture of the coating layer weremade using impregnating (solvating) agents to control the swelling ofthe drug-ion exchange resin complex. Other patents describing variationsof this type of product are referenced in US Published PatentApplication No. 2003/0099711 A1, section 0006.

Further, Kelleher et al. in U.S. Pat. No. 4,996,047 describe using adrug content above a specified value in the drug-ion exchange resincomplex to avoid the swelling of the drug-ion exchange resin complex andthereby minimizing the rupture of the coating. Umemoto et al., describein U.S. Pat. No. 5,368,852 that despite the use of impregnating agents,certain preservatives used in the liquid preparation tend to cause therupture of the diffusion barrier coating of the drug-ion exchange resincomplex. Umemoto et al. reported overcoming the rupture of the coatingmembrane by use of a preservative that did not cause the rupture.

Another patent, U.S. Pat. No. 6,001,392 granted Dec. 14, 1999 describescertain acrylate based (e.g., EUDRAGIT polymer system) and ethylcellulose (e.g., SURELEASE, AQUACOAT) polymers for coating a drug-ionexchange resin complex using either a solvent or aqueous based coatingto achieve sustained release of the drug from the drug-ion exchangeresin complex. No meaningful data is disclosed regarding the integrityof the coating film. Further, there is no reported data or evidence ofprolonged release of the drug from the coated drug-ion exchange resincomplex beyond about 12 hours. A more recently Published PatentApplication No. US 2003/0099711 A1, describes using an ethyl cellulosepolymer in an aqueous based coating system. This publication furtherdescribes use of an enteric coating as an optional added coating todelay the drug release. There have been literature-reported drawbacks ofusing ethyl cellulose based aqueous dispersions as coatings for drug-ionexchange resin complexes.

Similarly, there have been drawbacks associated with previously usedpolymers of acrylate and methacrylate-based aqueous dispersion coatingsystems for coating drug-ion exchange resin complex. Amongst theseshortcomings observed is significant tackiness upon application of thecoating and during curing, which complicates the coating process ofdrug-ion exchange resin complexes and/or requires the addition offurther components such as an anti-tacking material to counteract thisundesirable property.

SUMMARY OF THE INVENTION

The invention provides pharmaceutical preparations comprising drug(s)bound to an ion-exchange resin to provide a drug-ion exchange resincomplex, admixing of such complex with a release retardantwater-insoluble polymer, and coating of such admixture with a highlyflexible, substantially tack-free, non-ionic, water-insoluble,water-permeable diffusion membrane which is preferably aqueous-based andprovides a coating membrane that maintains its film integrity, andfurther provides controllable modified release of the activepharmaceutical(s) in the gastrointestinal tract for a duration of up toabout 24 hours.

In one aspect, the present invention provides ingestible pharmaceuticalcompositions comprising substantially tack free, non-ionic,water-permeable diffusion barrier coatings for drug-ion exchange resincomplexes that need not be based upon the use of organic solvents todissolve the coating composition, do not use either ethyl cellulose oracrylate based polymers compositions or other standard coatingsheretofore used for coating ion exchange drug resin complexes, do notrequire the use of impregnating (solvating) agents, provide excellentintegral film coatings, and can provide prolonged, programmable releaseof drugs from the drug-ion exchange resin complexes of up to about 24hours.

In another aspect, the present invention provides pharmaceuticalcompositions comprising water-permeable diffusion barrier coatings for adrug-ion exchange resin complex that are water based, provide highlyflexible coatings that are applied in substantially non-tacky form,which facilitates processing of such coatings, in the presence ofacceptable plasticizer levels and maintain the coating film integrityand minimize fracturing of the coating layer even after being subjectedto severe physical stress, including the compression step of a tabletingoperation.

In still another aspect, the present invention provides a highlyflexible coating that has the potential benefit of reducing thedrug-abuse of narcotics or control drug substances. The flexible coatingcan reduce the ability of the subjects to get instant “high” by makingit more difficult to break the barrier coating by chewing or othermechanical means due to the increased resistance of such flexiblecoating to easy rupture.

In a further aspect, the present invention provides oral pharmaceuticalcompositions comprising a drug-ion exchange resin complex that does notneed an enteric coating to provide prolonged release up to about 24hours.

In yet another aspect, the present invention provides oralpharmaceutical compositions comprising a drug-ion exchange resin complexthat can be formulated to give customizable, programmable release of theone or more drugs from such complexes by combining the application of arelease retardant in combination with a water-permeable diffusionbarrier coating that is aqueous-based and which are not believedheretofore to have been used for coating films for drug-ion exchangeresin complexes.

A further desirable advantage, previously reported when using ionexchange resins, is to provide a reduction of undesirable tastessometimes associated with an orally ingestible formulation, whereunbearable or bad taste of the active drug may be a drawback to therecommended drug ingestion regimen.

Another aspect of the present invention is to provide a method ofmanufacture of drug-ion exchange resin complexes that provideflexibility, higher drug binding efficiency, and drug loading andprocessing benefits to produce such complexes.

It has been observed by the inventors that use of heretofore known filmcoatings of an acrylate-based EUDRAGIT polymer system may lead toagglomeration of the particles during application and/or curing,particularly high-temperature curing. Further, such acrylate-basedpolymer systems have been observed by the inventors to causeagglomeration and color migration in the presence of colorants in anorally ingestible liquid suspension, upon storage thereof for over aboutone month. Further, the inventors have observed that ethylcellulose-based coating systems cause flocculation when in liquidsuspension, thereby creating a defective coating system.

Thus, the present invention addresses both art-recognized and what theinventors previously believe are unreported problems associated withprior art drug-ion exchange resin complexes. These and other advantagesof the present invention will be apparent from the following detaileddescription of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a coated drug-ion exchange resincomposition for further use in formulation with conventionalpharmaceutically acceptable components to provide ingestiblecompositions. The finished dose compositions may take the form of liquidpreparations such as suspensions or solid preparations such as tablets,capsules, liquigels, powders, wafers, strips, etc. In one preferredembodiment, the coating is an aqueous based coating. However, theinvention may utilize a non-aqueous, solvent-based system alone (as longas excess solvent is removed), or in conjunction with an aqueous basedcoating.

Controlled release particles containing pharmaceutically active drug canbe manufactured that are coated with an aqueous based system and providesafe products. The use of the water based coatings, the use of a releaseretardant, and methods of manufacture are disclosed.

The inventors have found that by using a drug-ion exchange resin havinga water-permeable diffusion barrier coating as described herein, aprolonged release of drug from the drug-ion exchange resin complex isobtained without the necessary use of water soluble impregnating(solvating) agents as these terms are defined in U.S. Pat. No.4,221,778.

The drug release pattern from the compositions of the present inventionmay be further controlled or modified by combining the drug and resin toform the drug-ion exchange resin complex matrix prior to the applicationof the water-permeable diffusion barrier coating. Water-insolublepolymers useful in the barrier coating include a single polymer ormixtures thereof, such as may be selected from polymers of ethylcellulose, polyvinyl acetate, cellulose acetate, polymers such ascellulose phthalate, acrylic based polymers and copolymers (such as, forexample, those available under EUDRAGIT brand name) or any combinationof such insoluble polymers or polymer systems herein defined as a“release retardant”. The water-permeable diffusion barrier coatingsystem with or without a “release retardant” may be formulated toachieve the desired length of time of drug release rate from suchdrug-ion exchange resin complexes. Such coating systems could be furthercustomized by the incorporation of individual or a combination ofhydrophilic or lipophilic plasticizers with a dispersion or suspensioncontaining the barrier coating polymer. Such plasticizers include, e.g.,propylene glycol, polyethylene glycol, triacetin, triethyl citrate,dibutyl sebacate, vegetable oil, lipids, etc.

Polyvinyl acetate, due to its high tensile strength in the presence of aplasticizer(s), provides a flexible coating film for use as thewater-permeable diffusion barrier coating that maintains its filmintegrity even when subjected to severe physical force and stress suchas during a compression step in a tabletting machine or the grindingaction of a coffee beans grinder, mill, etc. These coatings even withthe addition of a plasticizer remain substantially non-tacky andprocess-friendly during the coating operation in a Wurster fluid bed orother coating operation and do not cause agglomeration during thecoating of very fine particles of drug-ion exchange resins.Agglomeration (sometimes termed “caking” or “brick formation”) during acoating operation may otherwise impede the air flow, destroy flowpattern, and/or clog the spray nozzle, thereby increasing thepossibility of an imperfect and uneven coating of the drug-ion exchangeresin particles.

It has been found that, by employing the compositions described above,it is possible to obtain controlled release compositions that are highlyflexible and use a substantially tack-free coating system during coatingapplication and curing. Further, the compositions of the invention donot require the use of an impregnating (solvating) agent to control theswelling or otherwise impede the rupture of the coating membrane. Thus,the compositions of the present invention can provide programmable andprolonged release of drugs from drug-ion exchange resin complexes usingthe herein described water-based diffusion barrier coating systems.

The term “programmable release” is used to describe a pre-determinedrelease profile of drug from the drug-ion exchange resin complex for upto about 24 hours.

Due to the prolongation of the drug release of up to about 24 hours, thecompositions of the present invention have concomitant advantages:instead of taking two or three dosages per day, one may take aonce-a-day dose that would provide more consistent supply (release) ofthe drug that otherwise may have to be taken multiple times a day. Thisis especially beneficial in the case of small children, elderly people,or others, who have difficulty swallowing larger solid dosage forms suchas tablets or capsules.

The coated drug-ion exchange resins of the present invention areformulated into finished ingestible dosage forms such as a liquidsuspension or a fast disintegrating tablet that need not be swallowed.It has also been observed that for use in liquid compositions, the filmforming coating of the present invention for the drug-ion exchange resincomplex when formulated into a liquid suspension does not produceundesirable agglomerations and color migration of the suspendedparticles in the liquid in the presence of a colorant which is desirablyused in medicines to be taken by children. Therefore, such prolongedrelease compositions may enhance compliance.

As used herein, the term “modified release” refers to compositions ofthe invention which are characterized by having a drug release from adrug-ion exchange complex of the invention over a period of at leastabout 8 hours, and preferably up to about 24 hours. For a 24 hourrelease product, in one aspect, less than 50% of the drug is releasedfrom the drug-ion exchange resin complex of the invention at about 12hours from administration. In another aspect, less than 60% of the drugis released from the drug-ion exchange resin complex of the invention atabout 12 hours from administration. In still another aspect, less than70% of the drug is released from the drug-ion exchange resin complex atabout 12 hours. In still other embodiments, less than about 80% or moreof the drug is released from the drug-ion exchange resin at about 12hours. The term “modified release” may include, e.g., compositions whichextended release formulations, sustained release formulations, or delayrelease formulations.

As used herein in reference to numeric values provided herein, the term“about” may indicate a variability of as much as 10%.

A detailed description of the components of the compositions of thepresent invention follows:

Ion-Exchange Resin

Contemplated within the scope of the invention are pharmaceuticallyactive compounds safe for ingestion, which form a complex with anion-exchange resin and are manufactured in accordance with GoodManufacturing Practices (GMP) for bulk pharmaceutical chemicals.Typically, these compounds are designed for oral administration andadministration via a nasogastric tube.

Ion-exchange resins suitable for use in these preparations arewater-insoluble and comprise a preferably pharmacologically inertorganic and/or inorganic matrix containing functional groups that areionic or capable of being ionized under the appropriate conditions ofpH. The organic matrix may be synthetic (e.g., polymers or copolymers ofacrylic acid, methacrylic acid, sulfonated styrene, sulfonateddivinylbenzene), or partially synthetic (e.g. modified cellulose anddextrans). The inorganic matrix preferably comprises silica gel modifiedby the addition of ionic groups. Covalently bound ionic groups may bestrongly acidic (e.g., sulfonic acid, phosphoric acid), weakly acidic(e.g., carboxylic acid), strongly basic (e.g., primary amine), weaklybasic (e.g. quaternary ammonium), or a combination of acidic and basicgroups. In general, the types of ion exchangers suitable for use inion-exchange chromatography and for such applications as deionization ofwater are suitable for use in the controlled release of drugpreparations. Such ion-exchangers are described by H. F. Walton in“Principles of Ion Exchange” (pp: 312-343) and “Techniques andApplications of Ion-Exchange Chromatography” (pp: 344-361) inChromatography. (E. Heftmann, editor), van Nostrand Reinhold Company,New York (1975). Ion exchange resins that can be used in the presentinvention have exchange capacities of about 6 milliequivalents(meq)/gram and preferably about 5.5 meq/gram or below.

Typically the size of the ion-exchange particles is from about 5 micronsto about 750 microns, preferably the particle size is within the rangeof about 40 microns to about 250 microns for liquid dosage formsalthough particles up to about 1,000 micron can be used for solid dosageforms, e.g., tables and capsules. Particle sizes substantially below thelower limit are generally difficult to handle in all steps of theprocessing. Generally, uncoated drug-ion exchange resin particles of theinvention will tend to be at the lower end of this range, whereas coateddrug-ion exchange resin particles of the invention will tend to be atthe higher end of this range. However, both uncoated and coated drug-ionexchange resin particles may be designed within this size range.

Commercially available ion-exchange resins having a spherical shape anddiameters up to about 1,000 microns are gritty in liquid dosage formsand have a greater tendency to fracture when subjected todrying-hydrating cycles. Moreover, it is believed that the increaseddistance that a displacing ion must travel in its diffusion into theselarge particles, and the increased distance the displaced drug musttravel in its diffusion out of these large particles, cause a measurablebut not readily controlled prolongation of release even when thedrug-ion exchange resin complexes are uncoated. Release of drug fromuncoated drug-ion exchange resin complexes with particle sizes in theapproximate range of 40 microns to 250 microns is relatively rapid.Satisfactory control of the drug release from such complexes is achievedby the applied diffusion barrier coating and can be modified by theinclusion of a release retardant as described herein.

Both regularly and irregularly shaped particles may be used as resins.Regularly shaped particles are those particles that substantiallyconform to geometric shapes such as spherical, elliptical, cylindricaland the like, which are exemplified by Dow XYS-40010.00 and DowXYS-40013.00 (The Dow Chemical Company). Irregularly shaped particlesare all particles not considered to be regularly shaped, such asparticles with amorphous shapes and particles with increased surfaceareas due to surface channels or distortions. Irregularly shapedion-exchange resins of this type are exemplified by Amberlite IRP-69(Rohm and Haas). Two of the preferred resins of this invention areAmberlite IRP-69 and Dow XYS-40010.00. Both are sulfonated polymerscomposed of polystyrene cross-linked with about 8% of divinylbenzene,with an ion-exchange capacity of about 4.5 to 5.5 meq/g of dry resin(H⁺-form). Their essential difference is in physical form. AmberliteIRP-69 consists of irregularly shaped particles with a size range ofabout 5 microns to about 149 microns produced by milling the parentlarge size spheres of Amberlite IRP-120. The Dow XYS-40010.00 productconsists of spherical particles with a size range of 45 microns to 150microns.

Other suitable ion-exchange resins include anion exchange resins, suchas have been described in the art and are commercially available. Theseresins are particularly well suited for use with acidic drugs including,e.g., nicotinic acid, mefanimic acid, indomethacin, diclofenac,repaglinide, ketoprofen, ibuprofen, valproic acid, lansoprazole,ambroxol, omeprazole, acetominophen, topiramate, and carbemazepine,pentobarbital, warfarin, triametrene, and prednisolone, as well asprodrugs, salts, isomers, polymorphs, and solvates thereof, as well asother drugs identified herein and/or known in the art.

An example of an anion exchange resin is a cholestyramine resin, astrong base type 1 anion exchange resin powder with a polystyrene matrixand quarternary ammonium functional groups. The exchangeable anion isgenerally chloride which can be exchanged for, or replaced by, virtuallyany anionic species. A commercially available Cholestyramine resins isPUROLITE™ A430MR resin. As described by its manufacturer, this resin hasan average particle size range of less than 150 microns, a pH in therange of 4-6, and an exchange capacity of 1.8-2.2 eq/dry gm. Anotherpharmaceutical grade cholestyramine resin is available as DUOLITE™AP143/1094 [Rohm and Haas], described by the manufacturer as having aparticle size in the range of 95%, less than 100 microns and 40%, lessthan 50 microns. The commercial literature from the suppliers of theseand other resin is incorporated herein by reference (PUROLITE A-430 MR;DOW Cholestryramine USP, Form No. 177-01877-204, Dow Chemical Company;DUOLITE AP143/1083, Rohm and Haas Company, IE-566EDS—February 06).

Cation exchange resins, e.g., AMBERLITE IRP-69, are particularly wellsuited for use with drugs and other molecules having a cationicfunctionality, including, e.g., acycloguanosine, tinidazole,deferiprone, cimetidine, oxycodone, remacemide, nicotine, morphine,hydrocodone, rivastigmine, dextromethorphan, propanolol, betaxolol,4-aminopyridine, chlorpheniramine, paroxetine, duloxetine HCl,atomoxetine HCl, risperidone, atovaquone, esmolol, naloxone,phenylpropranolamine, gemifloxacin, oxymorphone, hydromorphone,nalbupherin, and O-desmethylvenlafaxine, as well as prodrugs, salts,isomers, polymorphs, and solvates thereof, as well as other drugsidentified herein and/or known in the art. Cationic exchange resins arereadily selected for use of these basic drugs or other drugs identifiedherein and/or are those which are known to those of skill in the art.

The selected ion-exchange resins may be further treated by themanufacturer or the purchaser to maximize the safety for pharmaceuticaluse or for improved performance of the compositions. Impurities presentin the resins may be removed or neutralized by the use of commonchelating agents, anti-oxidants, preservatives such as disodium edetate,sodium bisulfate, and so on by incorporating them at any stage ofpreparation either before complexation or during complexation orthereafter. These impurities along with their chelating agent to whichthey have bound may be removed before further treatment of the ionexchange resin with a release retardant and diffusion barrier coating.

Drugs

The drugs that are suitable for use in these preparations in terms ofchemical nature are acidic, basic, amphoteric, or zwitterionicmolecules. Such drugs include small molecules, and selected largermolecules as well, including chemical moieties and biologicals, such as,e.g., a protein or a fragment thereof (e.g., a peptide, polypeptide,etc), enzyme, antibody or antibody fragment.

The drugs that are suitable for use in these preparations include drugsfor the treatment of respiratory tract disorders such as, for example,antitussive expectorants such as dihydrocodeine phosphate, codeinephosphate, noscapine hydrochloride, phenylpropanolamine hydrochloride,potassium guaiacolsulfonate, cloperastine fendizoate, dextromethorphanhydrobromide and cloperastine hydrochloride; bronchodilators such asdl-methylephedrine hydrochloride and dl-methylephedrine saccharinate;and antihistamines such as fexofenadine HCl- or dl-chlorpheniraminemaleate. Other drugs useful for the invention include drugs for thetreatment of digestive tract disorders such as, for example, digestivetract antispasmodics, including scopolamine hydrobromide, metixenehydrocloride and dicyclomine hydrochloride, drugs for the treatment ofcentral nervous system disorders such as, for example, antipsychoticdrugs including phenothiazine derivatives (chlorpromazine hydrochloride,eth.) and phenothiazine-like compounds (chlorprothexene hydrochloride,eth.) antianxiety drugs such as benzodiazepine derivatives(chlordiazepoxide hydrochloride, diazepam, etc.), alprazolam, etc.,antidepressants such as imipramine compounds (imipramine hydrochloride,etc.), respiradone, SSRIs like sertraline HCl, paroxitene HCl,venlafaxine HCl, etc., antipyretic analgesics such as sodium salicylate,and hypnotics such as phenobarbital sodium; opioid analgesics drugs suchas alfentanil, allyprodine, alphaprodine, anileridne, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,cyclazocine, desmorphine, dextromoramide, dexocine, diampromide,dihydrocodeine, dihydromorphine, dimexoxadol, dimepheptanol,dimethylthiambutene, dioxaphetly butyrate, dipipanone, eptazocine,ethotheptazine, ethylmethylthiambutene, ethylmorphine, etonitazenefentanyl, heroin, hydrocodone, hydromorphone, hydroxpethidine,isomethadone, ketobermidone, levallorphan, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol metazocine,methadone, metopon, morphine, morphine sulfate, myrophine, nalbuphine,narceine, cicomorphine, norlevorphanol, nomethadonel nalorphine,normophine, norpipanone, opium, oxycodone, ixmymorphone, papavretum,pentazocine, phenadoxone, phenmorphan, phenazocine, phenoperidine,iminodine, piritamide, propheptazine, promedol, properidine, propiram,proposyphene, sufenanil, tramadol, tiline, salts thereof, mixtures ofany of the foregoing, mixed mu-agonists/antagonists, mu-antagonistcombinations, and the like; and drugs for the treatment of respiratorysystem disorders such as, for example, coronary dilators includingetafenone hydrochloride, calcium antagonists such as verapamilhydrochloride, hypotensive drugs such as hydrazine hydrochloride,propranolol hydrochloride and clonidine hydrochloride, a peripheralvasodilators/vasoconstrictors such as tolazoline hydrochloride,respiradone, other respiratory agents such as predinisolone,prednisolone sodium phosphate, albuterol, albuterol sulfate,terbutaline, etc. Antibiotics may also be useful including macrolidessuch as, oleandomycin phosphate, tetracyclines such as tetracyclinehydrochloride, streptomycins such as fradiomycin, sulfate, andpenicillin drugs such as amoxicillin, dicloxacillin sodium,pivmecillinam hydrochloride and carbenicillinindanly sodium.Chemotherapeutic drugs may also be used including sulfa drugs such assulfisomidine sodium, antituberculosis drugs such as kanamycin sulfate,and antiprotozoan drugs such as amodiaquine hydrochloride. An excellentsustained releasing effect is obtained in basic drugs for therespiratory tract such as dihydrocodeine phosphate, dl-methyl-ephedrinehydrochloride and phenylpropanolamine hydrochloride. Acidic drugs thatcan be used in the present invention include, for example, dehydrocholicacid, diflunisal, ethacrynic acid, fenoprofen, furosemide, gemfibrozil,ibuprofen, naproxen, phenytoin, progencid, sulindac, theophylline,salicylic acid and acetylsalicylic acid. Basic drugs that can be used inthe present invention include, for example, acetophenazine,amitriptyline, amphetamine, benztropine, biperiden,bromodiphenhydramine, brompheniramine, carbinoxamine, chloperastine,chlorcyclizine, chorpheniramine, chlorphenoxamine, chlorpromazine,clemastine, clomiphene, clonidine, codeine, cyclizine, cyclobenzaprine,cyproheptadine, desipramine, dexbrompheniramine, dexchlorpheniramine,dextroamphetamine, dextromethorphan, dicyclomine, diphemanil,diphenhydramine, doxepin, doxylamine, ergotamine, fluphenazine,haloperidol, hydrocodone, hydroxychloroquine, hydroxyzine, hyoscyamine,imipramine, levopropoxyphene, maprotiline, meclizine, mepenzolate,meperidine, mephentermine, mesoridazine, metformin, methadone,methylepherdine, methdilazine, methscopolamine, methysergide,metoprolol, nortriptylene, noscapine, nylindrin, oxybutynin, oxycodone,oxymorphone, orphenadrine, papaverine, pentazocine, phendimetrazine,phentermine, phenylephrine, phenylpropanolamine, pyrilamine,tripelennamine, triprolidine, promazine, propoxyphene, propanolol,pseudoephedrine, pyrilamine, quinidine, scopolamine, dextromethorphan,chlorpheniramine and codeine. Amphoteric drugs that can be used in thepresent invention include for example, aminocaproic acid, aminosalicylicacid, hydromorphone, isoxurprine, levorphanol, melphalan, morphine,nalidixic acid, and paraaminosaliclic acid.

Other drugs that are contemplated include methylphenidate,dexmethylphenidate, oxymorphone, codeine, hydrocodone,chloropheniramine, niacin, aspirin, salts thereof, and combinationsthereof. Salts include, but are not limited to, methylphenidate HCl,dexmethylphenidate HCl, oxymorphone HCl, codeine phosphate, hydrocodonebitartrate, albuterol sulfate, albuterol phosphate, chlorpheniraminemaleate, dexchlorpheniramine maleate, metformin HCl, oxybutynin HCl,albuterol sulfate, saligenine hydrochloride, cetrizine hydrochloride,ranitidine HCl, all individually or in combinations.

Representative of other suitable classes of drugs and specific drugsthat may not have been mentioned here may be found in U.S. Pat. No.5,980,882 (columns 7 through 11), the disclosure of which isincorporated herein by reference. Further, pharmaceutically acceptableprodrugs, salts, isomers, polymorphs, and solvates of the drugsidentified above, are useful in the present invention. In addition, thefree base of the salts specifically listed may be substituted with otherpharmaceutically acceptable salts, or use as the free base, or a prodrugform.

Drug-Ion Exchange Resin Complexes

Binding of the selected drug or combination of drugs to the ion exchangeresin can be accomplished using methods known in the art. One ofordinary skill in the art with little or no experimentation can easilydetermine the appropriate method depending upon the drug. Typically fourgeneral reactions are used for binding of a basic drug, these are (a)resin (Na⁺-form) plus drug (salt form); (b) resin (Na⁺-form) plus drug(as free base); (c) resin (H⁺-form) plus drug (salt form); and (d) resin(H⁺-form) plus drug (as free base). All of these reactions except (d)have cationic by-products and these by-products, by competing with thecationic drug for binding sites on the resin, reduce the amount of drugbound at equilibrium. For basic drugs, stoichiometric binding of drug toresin is accomplished only through reaction (d).

Four analogous binding reactions can be carried out for binding anacidic drug to an anion exchange resin. These are (a) resin (Cl⁻-form)plus drug (salt form); (b) resin (Cl⁻-form) plus drug (as free acid);(c) resin (OH⁻-form) plus drug (salt form); (d) resin (OH⁻-form) plusdrug (as free acid). All of these reactions except (d) have ionicby-products and the anions generated when the reactions occur competewith the anionic drug for binding sites on the resin with the resultthat reduced levels of drug are bound at equilibrium. For acidic drugs,stoichiometric binding of drug to resin is accomplished only throughreaction (d). The binding may be performed, for example as a batch orcolumn process, as is known in the art.

Typically the drug-ion exchange resin complex thus formed is collectedby filtration and washed with appropriate solvents to remove any unbounddrug or by-products. The complexes can be air-dried in trays, in a fluidbed dryer, or other suitable dryer, at room temperature or at elevatedtemperature.

For preparing the complexes, the batch equilibration is the preferredpractice when loading a drug into finely divided ion exchange resinpowders. Due to its fine particle size, ion exchange resin does not lenditself to conventional columnar operations used with ion exchangeresins. The total ion exchange capacity represents the maximumachievable capacity for exchanging cations or anions measured underideal laboratory conditions. The capacity which will be realized whenloading a drug onto ion exchange resin will be influenced by suchfactors as the inherent selectivity of the ion exchange resin for thedrug, the drug's concentration in the loading solution and theconcentration of competing ions also present in the loading solution.The rate of loading will be affected by the activity of the drug and itsmolecular dimensions as well as the extent to which the polymer phase isswollen during loading.

When utilizing a batch or equilibrium process for loading a drug onto anion exchange resin, it is usually desirable to load as much as possibleof the substance of value onto the ion exchange resin. Complete transferof the drug from the loading solution is not likely in a singleequilibrium stage. Accordingly, more than one equilibration may berequired in order to achieve the desired loading onto the ion exchangeresin. The use of two or more loading stages, separating the resin fromthe liquid phase between stages, is a means of achieving maximum loadingof the drug onto the ion exchange resin although loss of drug from theliquid phase of the final stage occurs.

Although carefully controlled laboratory experiments are required toestablish precise loading and elution conditions, a few generalprinciples can be used. High loading capacity will be favored by highcharge density in the drug, A high loading rate is favored by lowermolecular weight. Higher drug concentrations in the loading solution,with a minimum of competing ions, will also favor higher adsorptioncapacity.

The amount of drug that can be loaded onto a resin will typically rangefrom about 1% to about 75% by weight of the drug-ion exchange resinparticles. A skilled artisan with limited experimentation can determinethe optimum loading for any drug resin complex. In one embodiment,loading of about 10% to about 40% by weight, more desirably, about 15%to about 30% by weight, of the drug-ion exchange resin particles can beemployed. Typical loadings of about 25% by weight of the drug-ionexchange resin particles can be advantageously employed.

Thus, in one aspect, the invention provides drug-ion exchange resincomplexes comprising a drug loaded in an ion exchange resin as describedherein. The drugs and ion exchange resins may be readily selected fromamongst those drugs and resins described herein. The invention furtherprovides drug-ion exchange resin matrixes defined as follows.

Release Retardants

The drug release rate from the compositions of the present invention maybe further prolonged or modified by treating the drug-ion exchange resincomplex prior to the application of the water-permeable diffusionbarrier coating described herein, with a release retardant which is awater-insoluble polymer or a combination of a water-insoluble polymers.

Advantageously, the release retardant does not form a separate layer onthe drug-ion exchange resin complex, but forms a matrix therewith.Examples of suitable release retardants include, for example, apolyvinyl acetate polymer or a mixture of polymers containing same(e.g., KOLLICOAT SR 30D), cellulose acetates, ethylcellulose polymers(e.g., AQUACOAT™ ECD-30 or SURELEASE™) acrylic based polymers orcopolymers (e.g., represented by the EUDRAGIT family of acrylic resins),cellulose phthalate, or any combination of such water-insoluble polymersor polymer systems, all herein defined as “release retardants”. Theseretardants when used, may further prolong or alter the release of thedrug from the coated drug-ion exchange resin complex and maximizeattaining the desired release profile. Further, use of a releaseretardant permits in some cases lowering the amount of coating thicknessneeded to attain a prolonged drug release of up to 24 hours. Theseretardants can be used in either substantially pure form or as acommercial preparation obtained from a vendor. The preferred releaseretardant is a polyvinyl acetate polymer as described herein or anacrylic polymer from the EUDRAGIT family. Examples of suitable acrylicpolymers from the EUDRAGIT family may include, e.g., a copolymercomprising ethyl acrylate and methyl methacrylate (e.g., EUDRAGITNE-30D), or EUDRAGIT RS, RL30D, RL100, or NE, which are largelypH-independent polymers; although less desirable, certain pH-dependentmembers of the EUDRAGIT polymer family, e.g., the L, S, and E, polymersmay be selected.

The quantity of polymer that is added as a release retardant typicallyranges from about 3% to about 30% or more by weight of the uncoateddrug-ion exchange resin particles. More preferably the releaseretardant, if used, is in the range from about 5% to about 20% and mostpreferably in the range of about 10% to about 15% by weight of theuncoated drug-ion exchange resin particles, depending on the nature ofthe drug-ion exchange resin complex and the desired release profile ofthe medicinal agent(s).

These release retardants can be added during the formation of thedrug-ion exchange resin complex either in the beginning, during themiddle, or after substantial amount of complex formation has takenplace. In the more preferred embodiment, the retardant is added afterthe formation of drug-ion exchange resin complex. Upon admixing, thedrug-ion exchange resin complex particles with the release retardant,the mixture is dried and milled appropriately. In some cases, themilling may be carried out before the complete drying of the complex andthen again further drying followed by milling to obtain the desiredcomplex characteristics.

Another embodiment is the use of an impregnating (solvating) agent as arelease retardant incorporated into the pharmaceutically acceptable drugion-exchange resin complex prior to addition of the aqueous basedcoating. This impregnating (solvating) agent is a hydrophilic (watersoluble) agent exemplified by those materials described for example inU.S. Pat. No. 4,221,778 and published US Patent Application PublicationNo. US 2003/009971 A1, the disclosures of which are incorporated hereinby reference. Specific examples of suitable impregnating agents includepropylene glycol, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone (e.g., KOLLIDON™ K30) mannitol, methyl cellulose,hydroxypropyl methylcellulose, hydroxypropyl cellulose, and sorbitol.

Coating System

The coating system used in the present invention provides severaladvantages in preparation of the coated drug-ion exchange resin complex.More particularly, the polymers used in the coating of the invention arewater-insoluble and generally non-ionic in nature. The coating polymersavoid problems associated with relatively high tackiness which areencountered with application and curing of prior art coating systems(including, e.g., ionic polymers and those of the EUDRAGIT™ brandpolymer system). These problems with tackiness of prior art systems havebeen found by the present inventors to result in undesirable clumping ofthe coated particles and to require additional processing to separateparticles coated with these polymers. Attempts to solve this problemhave been made previously in the art, including, e.g., the addition ofanti-tacking agents to prior art coating systems. However, such agentsdo not satisfactorily solve these problems. Further, the well-knownprior art coating systems based upon use of many of the EUDRAGIT™ brandpolymer (and ionic polymers) have been found by the present inventors tohave additional drawbacks for other reasons, as they cause physicalstability problems, including agglomeration and migration of color whena colorant is used for liquid suspension formulations.

The coating system of the present invention can be applied as asubstantially tack-free dispersion, without the clumping problemsassociated with certain prior art coating systems during the coatingprocess and during high temperature curing. Further, the coating systemof the invention provides a high tensile strength barrier coating.

In one embodiment, the barrier coating layer is about 5% to about 200%,by weight, of the uncoated drug-ion exchange resin complex. In anotherembodiment, the barrier coating layer is about 25% to about 50% byweight of the uncoated drug-ion exchange resin complex, about 30% toabout 45% by weight of the uncoated complex, or about 35 to about 40% byweight of the uncoated drug-ion exchange resin complex.

Suitably, the present invention provides a barrier coating comprising awater insoluble polymer comprising a polyvinyl acetate polymer, or ablend of polymers comprising a polyvinyl acetate polymer. In oneembodiment, the barrier coating further contains a plasticizer, whichcan facilitate uniform coating of the drug-ion exchange resin complexand enhances the tensile strength of the barrier coating layer.

The aqueous based coating dispersions of the present invention that areused to provide a diffusion barrier coating are characterized by havinga relatively low tackiness in either the absence or presence ofplasticizer(s) and provide a high percent elongation of the polymer film(elasticity) at break in the presence or absence of plasticizer(s). Morespecifically, the polymer film coating is characterized by exhibiting atackiness as measured by the Hossel method described by P. Hossel,Cosmetics and Toiletries, 111(8):73 (1996) at 20° C./80% RH and 30°C./75% RH of about 2 or less in the presence or absence of a plasticizerand preferably about 0.5 or less.

Use of a relatively low tack film barrier of the present invention usinga polyvinyl acetate (PVA) polymer facilitates more rapid and easierprocessing of the coating composition and permits use of lowerquantities of plasticizer. This provides for enhanced elongation(elasticity) and flexibility of the film coating, a desirable propertyof the polymer film without significantly increasing film tackiness toundesirable levels due to use of a plasticizer.

A coating system useful in the invention, preferably containing apolyvinyl acetate polymer, is characterized by having film-formingability at a relatively low temperature, i.e., about 20° C. or less,without a plasticizer. The combination of a plasticizer with a polyvinylacetate polymer system may further lower the film-forming temperature ofthe polyvinyl acetate system.

Thus, the selection criteria for the plasticizer incorporated into theaqueous based polymer dispersion composition is to enhance highflexibility or elongation (elasticity) of the film coating at breakmeasured by the texture analyzer TA-XT2 HiR (Stable Microsystems) and bythe method reported by the manufacturer in its literature [i.e.,Jan-Peter Mittwollen, Evaluation of the Mechanical Behavior of DifferentSustained Release Polymers, Business Briefing: Pharmagenerics, 2003, pp.1-3, BASF], of at least about 100%, of at least about 125% andpreferably in a range between about 150% to about 400% while notsubstantially increasing the tackiness of the polymer film greater thanabout 2 (wherein the film is measured by the Hossel method referencedabove independent of any composition on which it has been deposited).The higher elasticity ranges are usually achieved with coatings of thepresent invention through the use of a relatively small amount ofplasticizer. By using relatively small amount of plasticizer, theplasticizer does not achieve high enough levels to negatively affect theproperties of the coating. It has been found that these objectives areachieved by using a relatively lower percent by weight of the selectedplasticizer(s) based on the percent by weight of the solids in theaqueous based film forming polymer composition.

Generally, a plasticizer is used in the percent range, or a mixture ofplasticizers combine to total, about 2 to about 50% by weight of thecoating layer, more preferably about 2.5% to about 20% by weight of thecoating layer on the coated drug-ion exchange resin complex. Preferablya plasticizer in range of about 5% to about 10% by weight of the coatinglayer based on the coated complex provides the most desirableproperties.

Suitable plasticizers are water soluble and water insoluble. Examples ofsuitable plasticizers include, e.g., dibutyl sebacate, propylene glycol,polyethylene glycol, polyvinyl alcohol, triethyl citrate, acetyltriethyl citrate, acetyl tributyl citrate, tributyl citrate, triacetin,and Soluphor P, and mixtures thereof. Other plasticizers are describedin Patent Application Publication No. US 2003/0099711 A1, May 29, 2003,page 4 (0041) the disclosure of which is incorporated herein byreference.

The coating composition of the present invention is preferably appliedin the form of a polyvinyl acetate (PVA) polymer based aqueous coatingdispersion. The PVA is insoluble in water at room temperature. The PVAmay be used in either substantially pure form or as a blend. Acommercial blend contains primarily a polyvinyl acetate polymer, astabilizer, and minor amounts of a surfactant such as sodium laurylsulfate. More specifically, the preferred aqueous based coating solutionis KOLLICOAT SR 30 D (BASF Corporation) and whose composition is about27% PVA polymer, about 2.7% polyvinylpyrrolidone (PVP), about 0.3%sodium lauryl sulfate (solids content 30% w/w). The PVP and surfactanthelp stabilize the aqueous dispersion of the PVA. Generally, suchstabilizing components are present in an amount totaling less than about10% w/w, and preferably less than about 5% w/w. In one embodiment, if asubstantially pure form of PVA is used, it can be dissolved in asuitable non-aqueous solvent to provide a coating solution for the drugion-exchange resin complex.

In a particularly desirable embodiment, the inventors have found thatoptimal modified release is obtained when the KOLLICOAT SR-30D aqueousdispersion is cured. Preferably, the coating is cured for about 1 toabout 24 hours. In alternate embodiments, the coating is cured for about4 to about 16 hours, and preferably about 5 hours at high temperature,e.g., about 50° C. to about 65° C., and preferably about 60° C.

Where the barrier coating comprises a PVA polymer, the PVA polymer ispresent in an amount of about 70% to about 90% w/w of the final barriercoating layer, at least about 75%, at least about 80%, about 85% w/w ofthe final barrier coating layer.

Where the barrier coating also comprises PVP as a stabilizer component(e.g., as is present in KOLLICOAT™ SR 30D), the final barrier coatinglayer generally contains about 5 to about 10% w/w of polyvinylpyrrolidone.

The release rate of the present aqueous based polymer coatings of theinvention which are designed to provide finished dosage orallyingestible pharmaceutical compositions such as liquid suspension,tablets, etc. are tailored to provide the desired drug release profileover a period of about 8 to 24 hours, and preferably 12 to 24 hours.This programmable release rate may be controlled principally by twovariables, i.e., the diffusion barrier coating thickness of thepolymeric film coating and optionally, but preferred use of “a releaseretardant” component as described above added to the drug-ion exchangeresin complex to form a fine particulate matrix prior to the polymerfilm coating step. The release retardant is preferably a water insolublepolymer as previously described such as a PVA dispersion which has thesame or similar composition of solids as the preferred aqueous basedfilm forming coating polymer dispersion described herein used in thecoating step or an acrylic based polymer available commercially underthe EUDRAGIT™ brand name, manufactured by Rohm Pharma Polymers. Theproperties of different EUDRAGIT™ compositions commercially availableare described in literature from Rohm Pharma and are also described inU.S. Pat. No. 6,419,960 (column 10-11), the disclosure of which isincorporated herein by reference. Other water insoluble polymers includethose listed in column 10, lines 41-53 of U.S. Pat. No. 6,419,960 thedisclosure of which is incorporated herein by reference.

Finished Dose Formulations

The drug-ion exchange resin complexes of the present invention, canreadily be formulated with pharmaceutically acceptable excipientsaccording to methods well known to those of skill in the art. In oneembodiment, these formulations contain a substantially coated drug-ionexchange resin complex of the invention, optionally with a releaseretardant. In another embodiment, such formulations may also contain aselected amount of uncoated drug-ion exchange resin complex, optionallywith a release retardant as described herein. In certain formulations,mixtures of coated drug-ion exchange resin complexes and uncoateddrug-ion exchange resin complexes are present. These formulations maycontain any suitable ratio of coated to uncoated product.

For example, a formulation of the invention containing the activecomponent dextromethorphan desirably contains a mixture of a coateddrug-ion exchange resin complex of the invention and an uncoateddrug-ion exchange resin complex of the invention, in order to achievethe optimal release profile. The uncoated dextromethorphan-ion exchangeresin complex and the coated dextromethorphan-ion exchange resin complexmay be present in a ratio of 100:1 to 1:100 by weight. In certainembodiments, the ratio may be in about 30:70, about 10:1 to about 1:10,or about 2:1 to about 1:2, by weight.

In yet another embodiment, the formulations of the invention may containmore than one active component. For example, the formulation may containmore than one drug loaded into an ion exchange resin to form a complexof the invention. As another example, the formulation may contain afirst drug-ion exchange resin complex of the invention in combinationwith another active component (drug) which may be in a second drug-ionexchange resin complex of the invention. In still another example, theformulation may contain a drug-ion exchange resin complex of theinvention in combination with one or more active components which arenot in a drug-ion exchange resin complex.

The coated drug-ion exchange resin complex of the invention may beformulated for delivery by any suitable route including, e.g., orally,topically, intraperitoneally, transdermally, sublingually,intramuscularly, rectally, transbuccally, intranasally, liposomally, viainhalation, vaginally, intraoccularly, via local delivery (for example,by catheter or stent), subcutaneously, intraadiposally,intraarticularly, or intrathecally. Preferably, the complex isformulated for oral delivery.

The drug-ion exchange resin composition thus prepared may be stored forfuture use or promptly formulated with conventional pharmaceuticallyacceptable carriers to prepare finished ingestible compositions fordelivery orally, nasogastric tube, or via other means. The compositionsaccording to this invention may, for example, take the form of liquidpreparations such as suspensions, or solid preparations such ascapsules, tablets, caplets, sublinguals, powders, wafers, strips, gels,including liquigels, etc. In one embodiment, a tablet of the inventionis formulated as an orally disintegrating tablet. Such orally dissolvingtablets may disintegrate in the mouth in less than about 60 seconds.

The drug-ion exchange resin coated compositions may be formulated usingconventional pharmaceutically acceptable carriers or excipients and wellestablished techniques. Without being limited thereto, such conventionalcarriers or excipients include diluents, binders and adhesives (i.e.,cellulose derivatives and acrylic derivatives), lubricants (i.e.,magnesium or calcium stearate, or vegetable oils, polyethylene glycols,talc, sodium lauryl sulfate, polyoxy ethylene monostearate), thickeners,solubilizers, humectants, disintegrants, colorants, flavorings,stabilizing agents, sweeteners, and miscellaneous materials such asbuffers and adsorbents in order to prepare a particular pharmaceuticalcomposition. The stabilizing agents may include preservatives andanti-oxidants, amongst other components which will be readily apparentto one of ordinary skill in the art.

Suitable thickeners include, e.g., tragacanth; xanthan gum; bentonite;starch; acacia and lower alkyl ethers of cellulose (including thehydroxy and carboxy derivatives of the cellulose ethers). Examples ofcellulose include, e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxy methylcellulose, microcrystalline cellulose(MCC), and MCC with sodium carboxyl methyl cellulose. In one embodiment,tragacanth is used and incorporated in an amount of from about 0.1 toabout 1.0% weight per volume (w/v) of the composition, and morepreferably about 0.5% w/v of the composition. Xanthan gum is used in theamount of from about 0.025 to about 0.5% w/v and preferably about 0.25%w/v.

The sustained-release ion exchange resin compositions may include ahumectant composition to give the liquid greater viscosity andstability. Suitable humectants useful in the finished formulationsinclude glycerin, polyethylene glycol, propylene glycol and mixturesthereof.

The oral liquid compositions of the present invention may also compriseone or more surfactants in amounts of up to about 5.0% w/v andpreferably from about 0.02 to about 3.0% w/v of the total formulation.The surfactants useful in the preparation of the finished compositionsof the present invention are generally organic materials which aid inthe stabilization and dispersion of the ingredients in aqueous systemsfor a suitable homogenous composition. Preferably, the surfactants ofchoice are non-ionic surfactants such as poly(oxyethylene)(20) sorbitanmonooleate and sorbitan monooleate. These are commercially known asTWEENS and SPANS and are produced in a wide variety of structures andmolecular weights.

Whereas any one of a number of surfactants may be used, preferably acompound from the group comprising polysorbate copolymers(sorbitan-mono-9-octadecenoate-poly(oxy-1,2-ethanediyl)) is employed.This compound is also added functions to keep any flavors and sweetenershomogeneously dissolved and dispersed in solution.

Suitable polysorbates include polysorbate 20, polysorbate 40,polysorbate 80 and mixtures thereof. Most preferably, polysorbate 80 isemployed. The surfactant component will comprise from about 0.01 toabout 2.0% w/v of the total composition and preferably will compriseabout 0.1% w/v of the total weight of the composition.

A second emulsifer/surfactant useful in combination with polysorbatesmay be employed and is preferably a poloxamer such as Poloxamer 407.Poloxamer 407 has an HLB (hydrophilic/lipophilic balance) of about 22and is sold under the tradename Pluoronic-127 (BASF-NJ). The twosurfactants can be employed in substantially equivalent amounts. Forexample, the Poloxamer 407 and polysorbate 80 may each be employedtogether at levels of approximately from about 0.02 to about 4.0% w/v ofthe total weight of the formulation.

Aqueous suspensions may be obtained by dispersing the drug-ion exchangeresin compositions in a suitable aqueous vehicle, optionally with theaddition of suitable viscosity enhancing agent(s) (e.g., cellulosederivatives, xanthan gum, etc). Non-aqueous suspensions may be obtainedby dispersing the foregoing compositions in a suitable non-aqueous basedvehicle, optionally with the addition of suitable viscosity enhancingagent(s) (e.g., hydrogenated edible fats, aluminum state, etc.).Suitable non-aqueous vehicles include, for example, almond oil, arachisoil, soybean oil or soybean oil or fractionated vegetable oils such asfractionated coconut oil.

Useful preservatives include, but are not limited to, sodium benzoate,benzoic acid, potassium sorbate, salts of edetate (also known as saltsof ethylenediaminetetraacetic acid, or EDTA, such as disodium EDTA),parabens (e.g., methyl, ethyl, propyl or butyl-hydroxybenzoates, etc.),and sorbic acid. Amongst useful preservatives include chelating agentssome of which are listed above and other chelating agents, e.g.,nitrilotriacetic acid (NTA); ethylenediaminetetracetic acid (EDTA),hydroxyethylethylenediaminetriacetic acid (HEDTA),diethylenetriaminepentaacetic acid (DPTA), 1,2-Diaminopropanetetraaceticacid (1,2-PDTA); 1,3-Diaminopropanetetraacetic acid (1,3-PDTA);2,2-ethylenedioxybis[ethyliminodi(acetic acid)] (EGTA);1,10-bis(2-pyridylmethyl)-1,4,7,10-tetraazadecane (BPTETA);ethylenediamine (EDAMINE); Trans-1,2-diaminocyclohexane-N, N, N′,N′-tetraacetic acid (CDTA); ethylenediamine-N, N′-diacetate (EDDA);phenazine methosulphate (PMS); 2, 6-Dichloro-indophenol (DCPIP);Bis(carboxymethyl)diaza-18-crown-6 (CROWN); porphine; chlorophyll;dimercaprol (2, 3-Dimercapto-1-propanol); citric acid; tartaric acid;fumaric acid; malic acid; and salts thereof. The preservatives listedabove are exemplary, but each preservative must be evaluated in eachformulation, to assure the compatibility and efficacy of thepreservative. Methods for evaluating the efficacy of preservatives inpharmaceutical formulations are known to those skilled in the art.Preferred preservatives are the paraben preservatives include methyl,ethyl, propyl, and butyl paraben. Methyl and propyl paraben are mostpreferable. Preferably, both methyl and propyl paraben are present inthe formulation in a ratio of methyl paraben to propyl paraben of fromabout 2.5:1 to about 16:1, preferably 9:1.

In the instance where auxiliary sweeteners are utilized, the presentinvention contemplates the inclusion of those sweeteners well known inthe art, including both natural and artificial sweeteners. Thus,additional sweeteners may be chosen from the following non-limitinglist: Water-soluble sweetening agents such as monosaccharides,disaccharides and polysaccharides such as xylose, ribose, glucose,mannose, galactose, fructose, high fructose corn syrup, dextrose,sucrose, sugar, maltose, partially hydrolyzed starch, or corn syrupsolids and sugar alcohols such as sorbitol, xylitol, mannitol andmixtures thereof;

In general, the amount of sweetener will vary with the desired amount ofsweeteners selected for a particular liquid formulation. This amountwill normally be 0.001 to about 90% by weight, per volume of the finalliquid composition, when using an easily extractable sweetener. Thewater-soluble sweeteners described above, are preferably used in amountsof about 5 to about 70% by weight per volume, and most preferably fromabout 10 to about 50% by weight per volume of the final liquidcomposition. In contrast, the artificial sweeteners [e.g., sucralose,acesulfame K, and dipeptide based sweeteners] are used in amounts ofabout 0.005 to about 5.0% and most preferably about 0.01 to about 2.5%by weight per volume of the final liquid composition. These amounts areordinarily necessary to achieve a desired level of sweetness independentfrom the flavor level achieved from flavor oils.

Suitable flavorings include both natural and artificial flavors, andmints such as peppermint, menthol, artificial vanilla, cinnamon, variousfruit flavors, both individual and mixed, essential oils (i.e. thymol,eculyptol, menthol and methyl salicylate) and the like are contemplated.The amount of flavoring employed is normally a matter of preferencesubject to such factors as flavor type, individual flavor, and strengthdesired. Thus, the amount may be varied in order to obtain the resultdesired in the final product. Such variations are within thecapabilities of those skilled in the art without the need for undueexperimentation. The flavorings are generally utilized in amounts thatwill vary depending upon the individual flavor, and may, for example,range in amounts of about 0.01 to about 3% by weight per volume of thefinal composition weight.

The colorants useful in the present invention include the pigments suchas titanium dioxide that may be incorporated in amounts of up to about1% by weight per volume, and preferably up to about 0.6% by weight pervolume. Also, the colorants may include dyes suitable for food, drug andcosmetic applications, and known as D&C and F.D. & C. dyes and the like.The materials acceptable for the foregoing spectrum of use arepreferably water-soluble. Illustrative examples include indigoid dye,known as F.D. & C. Blue No. 2, which is the disodium salt of5,5′indigotindisulfonic acid. Similarly, the dye known as F.D. & C.Green No. 1 comprises a triphenylmethane dye and is the monosodium saltof 4-[4-N-ethylp-sulfobenzylamino)diphenylmethylene]-[1-(N-ethyl-N-p-sulfoniumbenzyl)-2,5-cyclohexadienimine].A full recitation of all F.D. & C. and D. & C. and their correspondingchemical structures may be found in the Kirk-Othmer Encyclopedia ofChemical Technology, in Volume 5, at Pages 857-884, which text isaccordingly incorporated herein by reference.

Suitable oils and fats that are usable would include partiallyhydrogenated vegetable or animal fats, such as coconut oil, palm kerneloil, beef tallow, lard, and the like. These ingredients are generallyutilized in amounts with respect to the comestible product of up toabout 7.0% by weight, and preferably up to about 3.5% by weight of thefinal product.

Wetting agents also may be employed in the inventive compositions tofacilitate the dispersion of any hydrophobic ingredients. Theconcentration of wetting agents in the composition should be selected toachieve optimum dispersion of the ingredient within the composition withthe lowest feasible concentration of wetting agent. It should beappreciated that an excess concentration of wetting agent may cause thecomposition, as a suspension, to flocculate. Those skilled in the artare well versed in suitable empirical methods to determine theappropriate wetting agents and concentrations to achieve optimumdispersion and avoid flocculation. Suitable wetting agents are listed inthe US Pharmacoepia 29.

In another aspect, the invention provides a product containing a coateddrug-ion exchange resin complex of the invention.

In some embodiments, the coated drug-ion exchange resin complexes of theinvention are in packs in a form ready for administration, e.g., ablister pack, a bottle, syringes, foil packs, pouches, or other suitablecontainer. In other embodiments, the compositions of the invention arein concentrated form in packs, optionally with the diluent required tomake a final solution for administration. In still other embodiments,the product contains a compound useful in the invention in solid formand, optionally, a separate container with a suitable suspension base orother carrier for the drug-ion exchange resin complex useful in theinvention.

In still other embodiments, the above packs/kits include othercomponents, e.g., a meter dose apparatus/device, instructions fordilution, mixing and/or administration of the product, other containers,nasogastric tubes, etc. Other such pack/kit components will be readilyapparent to one of ordinary skill in the art.

Devices have been described, and many are commercially available, whichprovide for metered drug administration, including controlled infusiondevices (e.g., for patient-controlled analgesia), metered-dose inhalersand implantable pumps. For example, various liquid metering devices forsqueezable bottles have been described [U.S. Pat. Nos. 6,997,358,3,146,919, filed in 1960, U.S. Pat. No. 3,567,079, filed in 1968, and inGB 2201395, filed in 1986.] A device for dispensing multiplecompositions is provided in U.S. Pat. No. 6,997,219.

Methods and apparatus for delivery of drugs through nasogastric tubesare well known to those of ordinary skill in the art. See, e.g., E.Bryson, “Drug Administration via Nasogastric Tube”, Nurs Times, 2001,Apr. 19-25 97(16):51. The present invention can be readily deliveredusing such devices. Suitable nasogastric tubes are availablecommercially and/or have been described. See, e.g., U.S. Pat. Nos.5,334,166; 5,322,073; 4,619,673; 4,363,323.

The following examples are provided to more specifically illustrate themodified release compositions of the present invention and not intendedto be limiting. They are for illustrative purposes only and it isrealized that changes and variations can be made without departing fromthe spirit and scope of the invention.

Examples 1 to 17 are illustrative of the preparation of typical coateddrug-ion exchange resins complexes of the present invention. Somesamples from the compositions described in these examples were furtherprocessed into finish dosage forms and others were stored for futureformulation and on-going stability testing under accelerated and roomtemperature conditions.

Example 18 illustrates the compositions of an orally disintegratingtablet using the compositions of the current invention.

Example 19 and 20 provide the compositions containing EUDRAGIT andAQUACOAT as coating compositions that resulted in color migration andcaused flocculation/agglomeration.

Example 21 and 22 illustrate formulations of the invention that reducethe abuse potential of the drugs using the coated drug-ion exchangeresins of the present invention.

Preparation of Coated Drug Resin Complex Example 1 Preparation of CoatedMorphine Resin Complex

Ingredient Quantity Morphine Resin Complex Morphine Sulfate 450 gPurified Water 5 L AMBERLITE IRP-69 RESIN 807 g KOLLICOAT SR-30D polymersystem 501 g Coated Morphine Resin Complex KOLLICOAT SR-30D polymersystem 952 g Triacetin 14 g Purified Water 533 g Morphine Resin Complex600 g

The morphine resin complex was prepared by first dissolving 450 g ofmorphine sulfate in 5 L of purified water, and then slowly adding 807 gof AMBERLITE™ IRP-69 resin with continuous mixing. The dispersion wasmixed for 4 hours and upon completion, allowed to settle beforedecanting the supernatant. The slurring/decanting process was repeatedtwice with sufficient amounts of purified water. The wet resin complexwas then dried in a VWR™ convection oven maintained at 50° C. untilmoisture content was about 25%. KOLLICOAT™ SR-30D of 501 g was thenslowly added to the wet resin complex in a Hobart type mixer (KitchenAid) to form a uniform mass. The wet mass was again dried at 50° C. in aVWR™ convection oven to the moisture content around 20%. The semi-driedgranules were then milled through a 40 mesh screen using a CO-MIL™ brandmill and continued drying under 50° C. until the moisture content wasbetween 4-6%. The dried granules were then milled through a 40 meshscreen using CO-MIL™ brand mill [QUADRO].

The coating solution was prepared by dispersing 952 g of KOLLICOAT™SR-30D, 14 g of triacetin in 533 g of purified water and mixing for 1hour. The coating process was performed in a VECTOR™ FLM-1 fluid bedprocessor by applying 1,350 g of the coating solution to 600 g ofMorphine Resin Complex using WURSTER process that resulted in 45% weightgain. The coating conditions were controlled at an inlet temperature of77-82° C., product temperature of 26-33° C., air flow of 17-18 cfm,nozzle pressure of 2.5 kg/cm², accelerator air pressure of 1.0 kg/cm²and spray rate of 5-8 g/min so that uniform coating was achieved. TheCoated Morphine Resin Complex was then placed at 60° C. for 5 hours forcuring.

Example 2 Preparation of Coated Oxycodone Resin Complex

Ingredient Quantity Oxycodone Resin Complex Oxycodone HCl 450 g PurifiedWater 8 L AMBERLITE IRP-69 resin 1,427 g KOLLICOAT SR-30D polymer system500 g Coated Oxycodone Resin Complex KOLLICOAT SR-30D polymer system 825g Triacetin 12 g Purified Water 462 g Oxycodone Resin Complex 600 g

The Oxycodone Resin Complex was prepared by first dissolving 450 g ofoxycodone HCl in 8 L of purified water, and then slowly adding 1,427 gof AMBERLITE™ IRP-69 resin with continuous mixing. The dispersion wasmixed for 4 hours and upon completion, allowed to settle beforedecanting the supernatant. The slurring/decanting process was repeatedtwice with sufficient amounts of purified water. The wet resin complexwas then dried in a VWR™ convection oven maintained at 50° C. untilmoisture content was about 15%. KOLLICOAT™ SR-30D of 500 g was thenslowly added to the wet resin complex in a Hobart type mixer (KitchenAid) to form a uniform mass. The wet mass was again dried at 50° C. VWR™convection oven to the moisture content around 12%. The semi-driedgranules were then milled through 40 mesh screen using CO-MIL™ brandmill and continued drying under 50° C. until the moisture content wasbetween 4-6%. The dried granules were then milled through 40 mesh screenusing CO-MIL™ brand mill.

The coating solution was prepared by dispersing 825 g of KOLLICOAT™SR-30D, 12 g of triacetin in 462 g of purified water and mixed for 1hour. The coating process was performed in a VECTOR™ FLM-1 fluid bedprocessor by applying 1,200 g of the coating solution to 600 g ofOxycodone Resin Complex using WURSTER process that resulted in 40%weight gain. The coating conditions were controlled at an inlettemperature of 70-80° C., product temperature of 25-31° C., air flow of16-17 cfm, nozzle pressure of 2.5-3.0 kg/cm², accelerator air pressureof 1.0 kg/cm² and spray rate of 3-5 g/min so that uniform coating wasachieved. The Coated Oxycodone Resin Complex was then placed at 60° C.for 5 hours for curing.

Example 3 Preparation of Coated Albuterol Resin Complex

Ingredient Quantity Albuterol Resin Complex Albuterol Sulfate 286 gPurified Water 8 L AMBERLITE IRP-69 resin 1837 g KOLLICOAT SR-30Dpolymer system 640 g Coated Albuterol Resin Complex KOLLICOAT SR-30Dpolymer system 952 g Triacetin 14 g Purified Water 533 g Albuterol ResinComplex 600 g

The Albuterol Resin Complex was prepared by first dissolving 286 g ofalbuterol sulfate in 8 L of purified water, and then slowly adding 1837g of AMBERLITE™ IRP-69 resin with continuous mixing. The dispersion wasmixed for 4 hours and upon completion, allowed to settle beforedecanting the supernatant. The slurring/decanting process was repeatedtwice with sufficient amounts of purified water. The wet resin complexwas then dried in a VWR™ convection oven maintained at 50° C. untilmoisture content was about 30%. KOLLICOAT™ SR-30D of 640 g was thenslowly added to the wet resin complex in a Hobart type mixer (KitchenAid) to form a uniform mass. The wet mass was again dried at 50° C. in aVWR™ convection oven to the moisture content around 25%. The semi-driedgranules were then milled through a 40 mesh screen using CO-MIL™ brandmill and continued drying under 50° C. until the moisture content wasbetween 4-6%. The dried granules were then milled through a 40 meshscreen using CO-MIL™ brand mill.

The coating solution was prepared by dispersing 952 g of KOLLICOAT™SR-30D, 14 g of triacetin in 533 g of purified water and mixing for 1hour. The coating process was performed in a VECTOR™ FLM-1 fluid bedprocessor by applying 1,350 g of the coating solution to 600 g ofAlbuterol Resin Complex using WURSTER process that resulted in 45%weight gain. The coating conditions were controlled at an inlettemperature of about 60° C., product temperature of 31-34° C., air flowof 18-19 cfm, nozzle pressure of 2.5 kg/cm², accelerator air pressure of1.0 kg/cm² and spray rate of 3-6 g/min so that uniform coating wasachieved. The Coated Albuterol Resin Complex was then placed at 60° C.for 5 hours for curing.

Example 4 Preparation of Coated Methylphenidate Resin Complex

Ingredient Quantity Methylphenidate Resin Complex Methylphenidate HCl500 g Purified Water 8 L AMBERLITE IRP-69 resin 1,306 g EUDRAGIT NE-30Dpolymer system 467 g Coated Methylphenidate Resin Complex KOLLICOATSR-30D polymer system 635 g Triacetin 9.5 g Purified Water 356 gMethylphenidate Resin Complex 600 g

The Methylphenidate Resin Complex was prepared by first dissolving 500 gof methylphenidate HCl in 8 L of purified water, and then slowly adding1,306 g of AMBERLITE™ IRP-69 resin with continuous mixing. Thedispersion was mixed for 4 hours and upon completion, allowed to settlebefore decanting the supernatant. The slurring/decanting process wasrepeated twice with sufficient amounts of purified water. The wet resincomplex was then dried in a VWR™ convection oven maintained at 50° C.until moisture content was about 20-30%. EUDRAGIT™ NE-30D of 467 g wasthen slowly added to the wet resin complex in a Hobart type mixer(Kitchen Aid) to form a uniform mass. The wet mass was then passedthrough a 10 mesh screen and again dried at 50° C. in a VWR™ convectionoven to the moisture content around 4-6%. The dried granules were thenmilled through a 40 mesh screen using CO-MIL™ brand mill.

The coating solution was prepared by dispersing 635 g of KOLLICOAT™SR-30D, 9.5 g of triacetin in 356 g of purified water and mixing for 1hour. The coating process was performed in a VECTOR™ FLM-1 fluid bedprocessor by applying 900 g of the coating solution to 600 g ofMethylphenidate Resin Complex using Wurster process that resulted in 30%weight gain. The coating conditions were controlled at an inlettemperature of 55-62° C., product temperature of 29-31° C., air flow of20-24 cfm, nozzle pressure of 2.5 kg/cm², accelerator air pressure of1.0 kg/cm² and spray rate of 4-6 g/min so that uniform coating wasachieved. The Coated Methylphenidate Resin Complex was then placed at60° C. for 5 hours for curing.

Example 5 Preparation of Coated Dextromethorphan Resin Complex

Ingredient Quantity Dextromethorphan Resin Complex Dextromethorphan HBr954 g Purified Water 8 L AMBERLITE IRP-69 resin 1,758 g KOLLIDON K-30polymer 116 g Purified Water 1,150 g Coated Dextromethorphan ResinComplex KOLLICOAT SR-30D polymer system 762 g Triacetin 11 g PurifiedWater 427 g Dextromethorphan Resin Complex 600 g

The Dextromethorphan Resin Complex was prepared by first dissolving 954g of dextromethorphan HBr in 8 L of purified water heated to 75-80° C.,and then slowly adding 1,758 g of AMBERLITE™ IRP-69 resin withcontinuous mixing while cooling down to room temperature. The dispersionwas mixed for 4 hours and upon completion, allowed to settle beforedecanting the supernatant. The slurring/decanting process was repeatedtwice with sufficient amounts of purified water. The wet resin complexwas then dried in a VWR™ convection oven maintained at 50° C. untilmoisture content was about 20-25%. In a separate container, KOLLIDONK-30 polymer (116 g) was dissolved in 1,150 g of purified water andslowly applied to the wet resin complex in a Hobart type mixer (KitchenAid) to form a uniform mass. The wet mass was then dried at 50° C. in aVWR™ convection oven to the moisture content was around 4-6%. The driedgranules were then milled through a 40 mesh screen using CO-MIL″ brandmill.

The coating solution was prepared by dispersing 762 g of KOLLICOAT™SR-30D polymer, 11 g of triacetin in 427 g of purified water and mixingfor 1 hour. The coating process was performed in a VECTOR™ FLM-1 fluidbed processor by applying 1,050 g of the coating solution to 600 g ofDextromethorphan Resin Complex using Wurster process that resulted in35% weight gain. The coating conditions were controlled at inlettemperature of 64-71° C., product temperature of 27-35° C., air flow of15-20 cfm, nozzle pressure of 2.5 kg/cm², accelerator air pressure of1.0 kg/cm² and spray rate of 4-6 g/min so that uniform coating wasachieved. The Coated Dextromethorphan Resin Complex was then placed at60° C. for 5 hours for curing.

Example 6 Preparation of Coated Codeine Resin Complex

Ingredient Quantity Codeine Resin Complex Codeine Phosphate 500 gPurified Water 5 kg AMBERLITE IRP-69 resin 1,856 g EUDRAGIT NE-30Dpolymer system 668 g Purified Water 1,150 g Coated Codeine Resin ComplexKOLLICOAT SR-30D polymer 635 g Triacetin 9.5 g Purified Water 356 gCodeine Resin Complex 600 g

The Codeine Resin Complex was prepared by first dissolving 500 g ofcodeine phosphate in 5 kg of purified water, and then slowly adding1,856 g of AMBERLITE™ IRP-69 resin with continuous mixing. Thedispersion was mixed for 4 hours and upon completion, allowed to settlebefore decanting the supernatant. The slurring/decanting process wasrepeated twice with sufficient amounts of purified water. The wet resincomplex was then dried at VWR™ convection oven maintained at 50° C.until moisture content was about 20-30%. EUDRAGIT™ NE-30D polymer system(668 g) was mixed with 1,150 g of purified water and then slowly addedto the wet resin complex in a Hobart type mixer (Kitchen Aid) to form auniform mass. The wet mass was dried at 50° C. in a VWR™ convection ovento the moisture content around 3-7%. The dried granules were then milledthrough 40 mesh screen using CO-MIL™ brand mill.

The coating solution was prepared by dispersing 635 g of KOLLICOAT™SR-30D polymer, 9.5 g of triacetin in 356 g of purified water and mixingfor 1 hour. The coating process was performed in a VECTOR™ FLM-1 fluidbed processor by applying 900 g of the coating solution to 600 g ofCodeine Resin Complex using Wurster process that resulted in 30% weightgain. The coating conditions were controlled at an inlet temperature of54-68° C., product temperature of 30-35° C., air flow of 19-23 cfm,nozzle pressure of 2.5 kg/cm², accelerator air pressure of 1.0 kg/cm²and spray rate of 4-6 g/min so that uniform coating was achieved. TheCoated Codeine Resin Complex was then placed at 60° C. for 5 hours forcuring.

Example 7 Preparation of Coated Tramadol Resin Complex

Ingredient Quantity Tramadol Resin Complex Tramadol HCl 500 g PurifiedWater 8 L AMBERLITE IRP-69 resin 1,345 g KOLLICOAT SR-30D polymer 467 gCoated Tramadol Resin Complex KOLLICOAT SR-30D polymer 762 g Triacetin11 g Purified Water 427 g Tramadol Resin Complex 600 g

The Tramadol Resin Complex was prepared by first dissolving 500 g oftramadol HCl in 8 L of purified water, and then slowly adding 1,345 g ofAMBERLITE™ IRP-69 resin with continuous mixing. The dispersion was mixedfor 4 hours and upon completion, allowed to settle before decanting thesupernatant. The slurring/decanting process was repeated twice withsufficient amounts of purified water. The wet resin complex was thendried in a VWR™ convection oven maintained at 50° C. until moisturecontent was about 25%. KOLLICOAT™ SR-30D polymer (467 g) was then slowlyadded to the wet resin complex in a Hobart type mixer (Kitchen Aid) toform a uniform mass. The wet mass was again dried in a 50° C. VWR™convection oven to the moisture content around 20%. The semi-driedgranules were then milled through a 40 mesh screen using CO-MIL™ brandmill and continued drying under 50° C. until the moisture content wasbetween 4-6%. The dried granules were then milled through a 40 meshscreen using CO-MIL™ brand mill.

The coating solution was prepared by dispersing 762 g of KOLLICOAT™SR-30D polymer, 11 g of triacetin in 427 g of purified water and mixingfor 1 hour. The coating process was performed in a VECTOR™ FLM-1 fluidbed processor by applying 1,050 g of the coating solution to 600 g ofTramadol Resin Complex using Wurster process that resulted in 35% weightgain. The coating conditions were controlled at an inlet temperature ofabout 60-66° C., product temperature of 25-33° C., air flow of 16-19cfm, nozzle pressure of 2.5 kg/cm², accelerator air pressure of 1.0kg/cm² and spray rate of 4-5 g/min so that uniform coating was achieved.The Coated Tramadol Resin Complex was then placed at 60° C. for 5 hoursfor curing.

Example 8 Preparation of Coated Pseudoephedrine Resin Complex

Ingredient Quantity Pseudoephedrine Resin Complex Pseudoephedrine HCl857 g Purified Water 5 L AMBERLITE IRP-69 resin 1,589 g KOLLICOAT SR-30Dpolymer system 668 g Coated Pseudoephedrine Resin Complex KOLLICOATSR-30D polymer system 825 g Triacetin 12 g Purified Water 462 gPseudoephedrine Resin Complex 600 g

The Pseudoephedrine Resin Complex was prepared by first dissolving 857 gof pseudoephedrine HCl in 5 L of purified water, and then slowly adding1,589 g of AMBERLITE™ IRP-69 resin with continuous mixing. Thedispersion was mixed for 4 hours and upon completion, allowed to settlebefore decanting the supernatant. The slurry was filtered and rinsed 3times with sufficient amounts of purified water. The wet resin complexwas then dried in a VWR™ convection oven maintained at 50° C. untilmoisture content was about 25%. KOLLICOAT™ SR-30D polymer (668 g) wasthen slowly added to the wet resin complex in a Hobart type mixer(Kitchen Aid) to form a uniform mass. The wet mass was again dried at50° C. in a VWR™ convection oven to the moisture content around 30%. Thesemi-dried granules were then milled through a 40 mesh screen usingCO-MIL™ brand mill and continued drying under 50° C. until the moisturecontent was between 4-6%. The dried granules were then milled through a40 mesh screen using CO-MIL™ brand mill.

The coating solution was prepared by dispersing 825 g of KOLLICOAT™SR-30D polymer, 12 g of triacetin in 462 g of purified water and mixingfor 1 hour. The coating process was performed in a VECTOR™ FLM-1 fluidbed processor by applying 1,200 g of the coating solution to 600 g ofPseudoephedrine Resin Complex using Wuster process that resulted in 40%weight gain. The coating conditions were controlled at an inlettemperature of about 68-72° C., product temperature of 26-32° C., airflow of 16-19 cfm, nozzle pressure of 2.5 kg/cm², accelerator airpressure of 1.0 kg/cm² and spray rate of 4-6 g/min so that uniformcoating was achieved. The Coated Pseudoephedrine Resin Complex was thenplaced at 60° C. for 5 hours for curing.

Example 9 Preparation of Coated Phenylephrine Resin Complex

Ingredient Quantity Phenylephrine Resin Complex Phenylephrine HCl 400 gPurified Water 8 L AMBERLITE IRP-69 resin 1,165 g KOLLICOAT SR-30Dpolymer system 467 g Coated Phenylephrine Resin Complex KOLLICOAT SR-30Dpolymer system 825 g Triacetin 12 g Purified Water 462 g PhenylephrineResin Complex 600 g

The Phenylephrine Resin Complex was prepared by first dissolving 400 gof phenylephrine HCl in 8 L of purified water, and then slowly adding1,165 g of AMBERLITE™ IRP-69 resin with continuous mixing. Thedispersion was mixed for 4 hours and upon completion, allowed to settlebefore decanting the supernatant. The slurring/decanting process wasrepeated twice with sufficient amounts of purified water. The wet resincomplex was then dried in a VWR™ convection oven maintained at 50° C.until moisture content was about 25%. KOLLICOAT™ SR-30D polymer system(467 g) was then slowly added to the wet resin complex in a Hobart typemixer (Kitchen Aid) to form a uniform mass. The wet mass was again driedat 50° C. in a VWR™ convection oven to the moisture content around 30%.The semi-dried granules were then milled through a 40 mesh screen usingCO-MIL™ brand mill and continued drying under 50° C. until the moisturecontent was between 4-6%. The dried granules were then milled through a40 mesh screen using CO-MIL™ brand mill.

The coating solution was prepared by dispersing 825 g of KOLLICOAT™SR-30D polymer system, 12 g of triacetin in 462 g of purified water andmixing for 1 hour. The coating process was performed in a VECTOR™ FLM-1fluid bed processor by applying 1,200 g of the coating solution to 600 gof Phenylephrine Resin Complex using Wurster process that resulted in40% weight gain. The coating conditions were controlled at an inlettemperature of about 60-72° C., product temperature of 25-34° C., airflow of 16-19 cfm, nozzle pressure of 2.5 kg/cm², accelerator airpressure of 1.0 kg/cm² and spray rate of 4-6 g/min so that uniformcoating was achieved. The Coated Phenylephrine Resin Complex was thenplaced at 60° C. for 5 hours for curing.

Example 10 Preparation of Coated Hydrocodone Resin Complex

Ingredient Quantity Hydrocodone Resin Complex Hydrocodone Bitartrate 450g Purified Water 8 kg AMBERLITE IRP-69 resin 1,407 g KOLLICOAT SR-30Dpolymer system 500 g Coated Hydrocodone Resin Complex KOLLICOAT SR-30Dpolymer system 952 g Triacetin 14 g Purified Water 533 g HydrocodoneResin Complex 600 g

The Hydrocodone Resin Complex was prepared by first dissolving 450 g ofhydrocodone Bitartrate in 8 kg of purified water, and then slowly adding1,407 g of AMBERLITE™ IRP-69 resin with continuous mixing. Thedispersion was mixed for 4 hours and upon completion, allowed to settlebefore decanting the supernatant. The slurring/decanting process wasrepeated twice with sufficient amounts of purified water. The wet resincomplex was then dried in a VWR™ convection oven maintained at 50° C.until moisture content was about 20-25%. KOLLICOAT™ SR-30D polymer (500g) was then slowly added to the wet resin complex in a Hobart type mixer(Kitchen Aid) to form a uniform mass. The wet mass was again dried in a50° C. VWR™ convection oven to the moisture content around 15-20%. Thesemi-dried granules were then milled through a 40 mesh screen usingCO-MIL™ brand mill and continued drying under 50° C. until the moisturecontent was between 3-7%. The dried granules were then milled through a40 mesh screen using CO-MIL™ brand mill.

The coating solution was prepared by dispersing 952 g of KOLLICOAT™SR-30D polymer, 14 g of triacetin in 533 g of purified water and mixedfor 1 hour. The coating process was performed in a VECTOR™ FLM-1 fluidbed processor by applying 1,050 g of the coating solution to 600 g ofHydrocodone Resin Complex using Wurster process that resulted in 35%weight gain. The coating conditions were controlled at an inlettemperature of about 55-66° C., product temperature of 26-32° C., airflow of 16-20 cfm, nozzle pressure of 2.5 kg/cm², accelerator airpressure of 1.0 kg/cm² and spray rate of 4-5 g/min so that uniformcoating was achieved. The Coated Hydrocodone Resin Complex was thenplaced at 60° C. for 5 hours for curing.

Example 11 Preparation of Coated Venlafaxine Resin Complex

Ingredient Quantity Venlafaxine Resin Complex Venlafaxine HCl 500 gPurified Water 5 L AMBERLITE IRP-69 resin 1,000 g EUDRAGIT NE-30Dpolymer system 467 g Coated Venlafaxine Resin Complex KOLLICOAT SR-30Dpolymer system 635 g Triacetin 9.5 g Purified Water 356 g VenlafaxineResin Complex 600 g

The Venlafaxine Resin Complex was prepared by first dissolving 500 g ofvenlafaxine HCl in 5 L of purified water, and then slowly adding 1,000 gof AMBERLITE™ IRP-69 resin with continuous mixing. The dispersion wasmixed for 4 hours and upon completion, allowed to settle beforedecanting the supernatant. The slurring/decanting process was repeatedtwice with sufficient amounts of purified water. The wet resin complexwas then dried in a VWR™ convection oven maintained at 50° C. untilmoisture content was about 25%. EUDRAGIT™ NE-30D polymer of 467 g wasthen slowly added to the wet resin complex in a Hobart type mixer(Kitchen Aid) to form a uniform mass. The wet mass was dried in a 50° C.VWR™ convection oven to the moisture content around 4-6%. The driedgranules were then milled through a 40 mesh screen using CO-MIL™ brandmill.

The coating solution was prepared by dispersing 635 g of KOLLICOAT™SR-30D polymer system, 9.5 g of triacetin in 356 g of purified water andmixing for 1 hour. The coating process was performed in a VECTOR™ FLM-1fluid bed processor by applying 900 g of the coating solution to 600 gof Venlafaxine Resin Complex using Wurster process that resulted in 30%weight gain. The coating conditions were controlled at an inlettemperature of 40-45° C., product temperature of 29-33° C., air flow of40 cfm and nozzle pressure of 2.5 kg/cm², accelerator air pressure of1.0 kg/cm² and spray rate of 4-7 g/min so that uniform coating wasachieved. The Coated Venlafaxine Resin Complex was then placed at 60° C.for 5 hours for curing.

Example 12 Preparation of Coated Oxybutynin Resin Complex

Ingredient Quantity Oxybutynin Resin Complex Oxybutynin Hydrochloride300 g Purified Water 8 L AMBERLITE IRP-69 Resin (anhydrous) 1586 gKOLLICOAT SR-30D polymer system 540 g Coated Oxybutynin Resin ComplexKOLLICOAT SR-30D polymer system 761.9 g Triacetin 11.4 g Purified Water426.7 g Oxybutynin Resin Complex 600 g

The Oxybutynin Resin Complex was prepared by first dissolving 300 g ofoxybutynin hydrochloride in 8 L of purified water, and then slowlyadding 1586 g of AMBERLITE™ IRP-69 resin with continuous mixing. The pHwas adjusted to 3.9. The dispersion was mixed for 4 hours, and uponcompletion, allowed to settle before decanting the supernatant. Theslurring/decanting process was repeated twice with sufficient amounts ofpurified water. The wet resin complex was then dried in a VWR™convention oven maintained at 50° C. until moisture content was about25%. KOLLICOAT™ SR-30D polymer system (540 g) was then slowly added tothe wet resin complex in a Hobart type mixer (Kitchen Aid) to form auniform mass. The wet mass was again dried in a 50° C. VWR™ conventionoven to the moisture content about 25%. The semi-dried granules werethen milled through a 40 mesh screen using CO-MIL™ and continued dryingat 50° C. until the moisture content was between 3-7%. The driedgranules were then milled through a 40 mesh screen using CO-MIL™.

The coating solution was prepared by dispersing 761.9 g of KOLLICOAT™SR-30D polymer, 11.4 g triacetin in 426.7 g of purified water and mixingfor 1 hour. The coating process was performed in a VECTOR™ FLM-1 fluidbed processor by applying 1050 g of the coating solution to 600 g ofOxybutynin Resin Complex using Wurster process, resulting in a 35%weight gain. The coating conditions were controlled at an inlettemperature of about 58-72° C., product temperature of 26-32° C., airflow of 16-20 cfm, nozzle pressure of 2.5 kg/cm², accelerator airpressure of 1.0 kg/cm² and a spray rate of 4-6 g/min, so that a uniformcoating was achieved. The Coated Oxybutynin Resin Complex was thenplaced at 60° C. for 5 hours for curing.

Example 13 Preparation of Coated Metformin Resin Complex

Ingredient Quantity Metformin Resin Complex Metformin HCl 225 g PurifiedWater 4 L AMBERLITE IRP-69 Resin (anhydrous) 735 g KOLLICOAT SR-30Dpolymer system 250 g Purified Water 150 g Coated Metformin Resin ComplexKOLLICOAT SR-30D polymer system 761.9 g Triacetin 11.4 g Purified Water426.7 g Metformin Resin Complex 600 g

The Metformin Resin Complex was prepared by first dissolving 225 g ofmetformin HCl in 4 L of purified water, and then slowly adding 735 g ofAMBERLITE™ IRP-69 resin with continuous mixing. The dispersion was mixedfor 4 hours and upon completion, allowed to settle before decanting thesupernatant. The slurring/decanting process was repeated twice withsufficient amounts of purified water. The wet resin complex was thendried in a VWR™ convection oven maintained at 50° C. until moisturecontent was about 25%. KOLLICOAT™ SR-30D (250 g) was first mixed with150 g of purified water and the mixture was then slowly added to the wetresin complex in a Hobart type mixer (Kitchen Aid) to form a uniformmass. The wet mass was again dried in a 50° C. VWR™ convection oven tothe moisture content about 20%. The semi-dried granules were then milledthrough a 40 mesh screen using CO-MIL™ brand mill and drying continuedat 50° C. until the moisture content was between 3-7%. The driedgranules were then milled through a 40 mesh screen using CO-MIL™ brandmill.

The coating solution was prepared by dispersing 761.9 g of KOLLICOAT™SR-30D polymer, 11.4 g triacetin in 426.7 g of purified water and mixingfor 1 hour. The coating process was performed in a VECTOR™ FLM-1 fluidbed processor by applying 1050 g of the coating solution to 600 g ofMetformin Resin Complex using WURSTER process, resulting in a 35% weightgain. The coating conditions were controlled at an inlet temperature ofabout 68-72° C., product temperature of 28-38° C., air flow of 16-24cfm, nozzle pressure of 2.5 kg/cm², accelerator air pressure of 1.0kg/cm² and a spray rate of 5-7 g/min, so that a uniform coating wasachieved. The Coated Metformin Resin Complex was then placed at 60° C.for 5 hours for curing.

Example 14 Preparation of Coated Ibuprofen Resin Complex

Ingredient Quantity Ibuprofen Resin Complex Ibuprofen 400 g PurifiedWater 8 L PUROLITE A430MR Resin 800 g KOLLICOAT SR-30D polymer system250 g Coated Ibuprofen Resin Complex KOLLICOAT SR-30D polymer system761.9 g Triacetin 11.4 g Purified Water 426.7 g Ibuprofen Resin Complex600 g

The Ibuprofen Resin Complex was prepared by first dissolving 400 g ofIbuprofen in 8 L of purified water (adjusted to pH>8 with 10N NaOH), andthen slowly adding 800 g of PUROLITE™ A430MR resin with continuousmixing. The dispersion was mixed for 4 hours and upon completion,allowed to settle before decanting the supernatant. Theslurring/decanting process was repeated twice with sufficient amounts ofpurified water. The wet resin complex was then dried in a VWR™convection oven maintained at 50° C. until the moisture content wasabout 25%. KOLLICOAT™ SR-30D (250 g) was then slowly added to the wetresin complex in a Hobart type mixer (Kitchen Aid) to form a uniformmass. The wet mass was again dried in a 50° C. VWR™ convection oven tothe moisture content of about 20%. The semi-dried granules were thenmilled through a 40 mesh screen using CO-MIL™ brand mill and drying wascontinued at 50° C. until the moisture content was between 4-6%. Thedried granules were again milled through a 40 mesh screen using CO-MIL™.

The coating solution was prepared by dispersing 761.9 g of KOLLICOAT™SR-30D polymer, 11.4 g triacetin in 426.7 g of purified water and mixingfor 1 hour. The coating process was performed in a VECTOR™ FLM-1 fluidbed processor by applying 1050 g of the coating solution to 600 g ofIbuprofen Resin Complex using Wurster process, resulting in a 35% weightgain. The coating conditions were controlled at an inlet temperature ofabout 55-70° C., product temperature of 28-33° C., air flow of 16-21cfm, nozzle pressure of 2.5 kg/cm², accelerator air pressure of 1.0kg/cm² and a spray rate of 4-7 g/min, so that a uniform coating wasachieved. The Coated Ibuprofen Resin Complex was then placed at 60° C.for 5 hours for curing.

Preparation of Suspension Example 15 Preparation of Albuterol Suspension

Ingredient Quantity Placebo Suspension Base Purified Water 500 g CitricAcid, anhydrous 4 g FD&C Yellow #6 0.032 g FD&C Red #40 0.072 g HighFructose Corn Syrup 42 600 g Methylparaben 3.6 g Propylparaben 0.4 gGlycerin 200 g Sucrose 300 g Starch 50.13 g Xanthan Gum 4.35 gStrawberry/Banana flavor 22.44 g QS Purified Water 1,742.45 g AlbuterolER Suspension Purified Water 100 g Polysorbate 80 0.55 g CoatedAlbuterol Resin Complex (from 5.54 g Example 3) Placebo Suspension Base435.6 g Purified Water QS 500 mL

Placebo Suspension Base was prepared by first dissolving 4 g of citricacid in 500 g of purified water in the main container, followed byadding 600 g of high fructose corn syrup and 300 g of sucrose to achievecomplete solution. In a separate container, 0.032 g of FD&C Yellow #6and 0.072 g of g of FD&C Red #40 were dissolved in sufficient amount ofpurified water and then transferred to the main container. The starch(50.13 g) was then slowly introduced to the main container under highspeed/shear mixing condition to achieve uniform dispersion. In anothercontainer, 200 g of glycerin was added and heated to 45-50° C. beforeadditions of 3.6 g of methylparaben and 0.4 g of propylparaben. Afterboth parabens were dissolved, the solution was then cooled to roomtemperature and 4.35 g of xanthan gum was slowly introduced to thesolution to form a uniform dispersion. The gum dispersion was thentransferred to the main container under high speed/shear mixingcondition to achieve uniform suspension. The 22.44 g ofstrawberry/banana flavor was added and the Placebo Suspension Base wasachieved by adjusting to final weight of 1,742.45 g with purified waterand mixed until uniform. To prepare the final suspension, 0.55 g ofpolysorbate 80 was dissolved in 100 g of purified water followed byaddition of 435.6 g of Placebo Suspension Base. The Coated AlbuterolResin Complex prepared as described in Example 3 (5.54 g) was thenslowly introduced to the above dispersion under gentle mixing condition.The final suspension was obtained by adjusting the volume to 500 mL withappropriate amount of purified water and mixed until uniform.

Example 16 Preparation Morphine Suspension

Ingredient Quantity Placebo Suspension Base Tartaric Acid 8 g FD&C Red#40 0.144 g Cherry Flavor 2.06 g High Fructose Corn Syrup 42 1,200 gMethylparaben 7.2 g Propylparaben 0.8 g Glycerin 400 g Sucrose 600 gAVICEL RC-591 microcrystalline cellulose 48 g Xanthan Gum 7.68 gPurified Water QS 3,484.91 g Morphine ER Suspension Purified Water 20 gSodium Metabisulfite 0.1 g Polysorbate 80 surfactant 0.11 g CoatedMorphine Resin Complex (from 3.2 g Example 1) Placebo Suspension Base87.12 g Purified Water QS 100 mL

Placebo Suspension Base was prepared by first dissolving 8 g of tartaricacid in appropriate amount of purified water in the main container,followed by adding 1,200 g of high fructose corn syrup and 600 g ofsucrose to achieve a complete solution. In a separate container, 0.144 gof FD&C Red #40 was dissolved in a sufficient amount of purified waterand then transferred to the main container. The AVICEL RC-591microcrystalline cellulose (48 g) was then slowly introduced to the maincontainer under high shear mixing condition to achieve uniformdispersion. In another container, 400 g of glycerin was added and heatedto 45-50° C. before additions of 7.2 g of methylparaben and 0.8 g ofpropylparaben. After both parabens were dissolved, the solution was thencooled to room temperature and 7.68 g of xanthan gum was slowlyintroduced to the solution to form a uniform dispersion. The gumdispersion was then transferred to the main container under highspeed/shear mixing condition to achieve uniform suspension. The 2.06 gof cherry flavor was added and the Placebo Suspension Base was achievedby adjusting to final weight of 3,484.91 g with purified water and mixeduntil uniform. To prepare the final suspension, 0.1 g of sodiummetabisulfite and 0.11 g of Polysorbate 80 surfactant were dissolved in20 g of purified water followed by addition of 87.12 g of PlaceboSuspension base. The Coated Morphine Resin Complex prepared according toExample 1 of 3.2 g was then slowly introduced to the above dispersionunder gentle mixing condition. The final suspension was obtained byadjusting the volume to 100 mL with appropriate amount of purified waterand mixed until uniform.

Example 17 Preparation Oxycodone Suspension

Ingredient Quantity Placebo Suspension Base Tartaric Acid 8 g FD&C Red#40 0.144 g Strawberry Flavor 2.06 g High Fructose Corn Syrup 42 1,200 gMethylparaben 7.2 g Propylparaben 0.8 g Glycerin 400 g Sucrose 600 gAvicel RC-591 microcrystalline cellulose 48 g Xanthan Gum 7.68 gPurified Water QS 3,484.91 g Oxycodone ER Suspension Purified Water 100g Sodium Metabisulfite 0.5 g Polysorbate 80 surfactant 0.55 g CoatedOxycodone Resin Complex (from 5.66 g Example 2) Placebo Suspension Base435.6 g Purified Water QS 500 mL

Placebo Suspension Base was prepared by first dissolving 8 g of tartaricacid in appropriate amount of purified water in the main container,followed by adding 1,200 g of high fructose corn syrup and 600 g ofsucrose to achieve complete solution. In a separate container, 0.144 gof FD&C Red #40 was dissolved in sufficient amount of purified water andthen transferred to the main container. The AVICEL RC-591microcrystalline cellulose (48 g) was then slowly introduced to the maincontainer under high shear mixing condition to achieve uniformdispersion. In another container, 400 g of glycerin was added and heatedto 45-50° C. before additions of 7.2 g of methylparaben and 0.8 g ofpropylparaben. After both parabens were dissolved, the solution was thencooled to room temperature and 7.68 g of xanthan gum was slowlyintroduced to the solution to form a uniform dispersion. The gumdispersion was then transferred to the main container under highspeed/shear mixing condition to achieve uniform suspension. The 2.06 gof strawberry flavor was added and the Placebo Suspension Base wasachieved by adjusting to final weight of 3484.91 g with purified waterand mixed until uniform. To prepare the final suspension, 0.5 g ofsodium metabisulfite and 0.55 g of polysorbate 80 surfactant weredissolved in 100 g of purified water followed by addition of 435.6 g ofPlacebo Suspension Base. The Coated Oxycodone Resin Complex preparedaccording to Example 2 (5.66 g) was then slowly introduced to the abovedispersion under gentle mixing condition. The final suspension wasobtained by adjusting the volume to 500 mL with appropriate amount ofpurified water and mixed until uniform.

Example 18 Orally Disintegrating Tablet Formulation Preparation ofCoated Dextromethorphan Resin Complex

Ingredient Quantity Dextromethorphan Resin Complex Dextromethorphan HBrUSP 954 g Purified Water 8 L AMBERLITE IRP-69 resin (anhydrous) 1,758 gKOLLIDON K-30 brand PVP 116 g Purified Water 1,151 g CoatedDextromethorphan Resin Complex KOLLICOAT SR-30D polymer system 635 gTriacetin 9.5 g Purified Water 356 g Dextromethorphan Resin Complex 600g

The Dextromethorphan Resin Complex was prepared by first dissolving 954g of dextromethorphan HBr in 8 L of purified water heated to 75-80° C.,followed by the addition of 1,758 g of AMBERLITE™ IRP-69 resin undergentle mixing for 4 hours. At the completion, the suspension was allowedto settle, decanted and rinsed with purified water twice and dried in anoven maintained at 50° C. until moisture was around 5%. The PVP solutionwas prepared by dissolving 116 g of KOLLIDON K-30 brand PVP in 1,151 gof purified water and the solution was slowly added to theDextromethorphan Resin Complex in a Hobart type mixer (Kitchen Aid) toform a uniform mass and dried at 50° C. until moisture is between 3-7%.The dried granules were then milled through a 40 mesh screen usingCo-Mil™ brand mill.

The coating solution was prepared by first gently mixing 635 g ofKOLLICOAT™ SR-30D polymer system, 9.5 g of triacetin and 356 g ofpurified water for 1 hour. The coating process was performed in VECTOR™FLM-1 fluid bed processor by applying 900 g of the coating solution to600 g of Dextromethorphan Resin Complex using Wurster process thatresulted in 30% weight gain. The coating conditions were controlled atan inlet temperature of 62-76° C., product temperature of 28-35° C., airflow of 16-20 cfm, nozzle pressure of 2.5 kg/cm², accelerator airpressure of 1.0 kg/cm² and spray rate of 4-6 g/min so that uniformcoating was achieved. The Coated Dextromethorphan Resin Complex was thenplaced at 60° C. for 5 hours for curing.

Preparation of Uncoated Dextromethorphan Resin Complex

An Uncoated Dextromethorphan Resin Complex was prepared as follows.

Ingredient Quantity Uncoated Dextromethorphan Resin ComplexDextromethorphan HBr USP 119.28 g Purified Water 1 L AMBERLITE IRP-69RESIN (anhydrous) 223.01 g

Uncoated Dextromethorphan Resin Complex was prepared by first dissolving119.28 g of dextromethorphan HBr in 1 L of purified water heated to75-80° C., followed by the addition of 223.01 g AMBERLITE IRP-69 resinunder gentle mixing for 4 hours. At the completion, the suspension wasallowed to settle, and was then decanted and rinsed with purified watertwice and dried in an oven maintained at 50° C. until the moisturecontent is around 5%. The dried resin complex was hand sieved through 40mesh screen.

Tablet Preparation

The Coated Dextromethorphan Resin and Uncoated Dextromethorphan Resin ofthis example were utilized in tablet preparation as follows.

Ingredient Quantity per tablet Quantity Uncoated Dextromethorphan Resin23.78 mg 4.76 g Coated Dextromethorphan Resin 72.70 mg 14.54 g CalciumSilicate 49 mg 9.8 g Zeopharm 3.5 mg 0.7 g Silicon Dioxide 5.0 mg 1.0 gMicrocrystalline Cellulose 24 mg 4.8 g Acesulfame K sugar substitute 2mg 0.4 g Aspartame 5 mg 1.0 g Peppermint 2.5 mg 0.5 g Crospovidone 15 mg3.0 g Mannitol 124 mg 24.8 g Mg Stearate 5 mg 1.0 g Total 331.48 mg66.30 g

A small batch of tablets were prepared by first adding quantities of theUncoated and Coated Dextromethorphan Resin, calcium silicate, zeopharm,silicon dioxide, microcrystalline cellulose, crospovidone, Acesulfame-Ksugar substitute, Aspartame and mannitol in the amounts as specified inthe above formulation to a blender and mixing for 10 minutes. Magnesiumstearate (1.0 g) was added to the powder blend and mixed for anadditional 3 minutes. The final blend was discharged into a RIMEK™tablet press equipped with ⅜″ standard concave tooling and tablets ofmoderate hardness (3-6 Kp tested by VANDERKAMP™ tablet hardness tester)were compressed.

Dissolution release rate of the oral disintegrating dextromethorphanextended release tablets of the invention was conducted in 900 mL 0.4MKH₂PO₄ at paddle, 50 rpm and the results of the tablets showedcomparable results to the ER suspension.

Example 19 Color Migration of Water Soluble Dyes in FinishedFormulations Having Drug-Ion Exchange Resin Complexes Coated withEUDRAGIT Brand Polymer Coating—Comparative Example

Dextromethorphan suspension prepared with uncoated and EUDRAGIT coatedDextromethorphan Resin Complex was observed to have color migration;this color migration was more pronounced at 40° C./75% RH as compared to25° C./60% RH.

Preparation of Uncoated and Coated Dextromethorphan Resin Complex

Ingredient Quantity Uncoated Dextromethorphan Resin ComplexDextromethorphan HBr USP 119.28 g Purified Water 1 L AMBERLITE IRP-69RESIN (anhydrous) 223.01 g

Uncoated Dextromethorphan Resin Complex was prepared by first dissolving119.28 g of dextromethorphan HBr in 1 L of purified water heated to75-80° C., followed by the addition of 223.01 g AMBERLITE IRP-69 resinunder gentle mixing for 4 hours. At the completion, the suspension wasallowed to settle, and was then decanted and rinsed with purified watertwice and dried in an oven maintained at 50° C. until the moisturecontent was around 5%. The dried resin complex was hand sieved through a40 mesh screen.

Ingredient Quantity Dextromethorphan Resin Complex Dextromethorphan HBrUSP 954.2 g Purified Water 8 L AMBERLITE IRP-69 RESIN (anhydrous) 1784.0g KOLLIDON K-30 polyvinyl pyrrolidone 116 g Purified Water 528.4 gCoated Dextromethorphan Resin Complex Eudragit RS-30D polymer system334.89 g Triethyl Citrate 20.25 g Talc 50.19 g Polysorbate 80 surfactant0.29 g Purified Water 292.2 g Dextromethorphan Resin Complex 600 g

The Dextromethorphan Resin Complex was prepared by first dissolving954.2 g of dextromethorphan HBr in 8 L of purified water heated to75-80° C., followed by the addition of 1784 g of AMBERLITE IRP-69 resinunder gentle mixing for 4 hours. At the completion, the suspension wasallowed to settle, decanted and rinsed with purified water twice anddried in an oven maintained at 50° C. until moisture was around 5%. ThePVP solution prepared by dissolving 116 g of KOLLIDON K-30 in 528.4 g ofpurified water was slowly added to the Dextromethorphan Resin Complex ina Hobart type mixer (Kitchen Aid) to form a uniform mass and dried at50° C. until moisture was between 3-7%. The dried granules were thenmilled through a 40 mesh screen using Co-Mil.

Coating solution was prepared by gently mixing 334.89 g of EudragitRS-30D polymer system, 0.29 g of polysorbate 80 surfactant, 20.25 g oftriethyl citrate and 292.2 g of purified water for 45 minutes, followedby addition of 50.19 g of talc and continued mixing for 1 hour. Thecoating process was performed in Glatt GPCG-1 fluid bed processor byapplying 698 g of the coating solution to 600 g of DextromethorphanResin Complex using WURSTER Process that resulted in 28.5% weight gain.The coated Dextromethorphan Resin Complex was placed at 60° C. for5-hour curing.

Preparation Dextromethorphan Suspension

Ingredient Quantity Placebo Suspension Base Citric Acid 6 g FD&C Yellow#6 0.03278 g Orange Flavor 2.01 g High Fructose Corn Syrup 42 600 gMethylparaben 3.6 g Propylparaben 0.6 g Propylene Glycol 100 g Sucrose300 g Tragacanth Gum 10.51 g Xanthan Gum 3.59 g Purified Water 1,015 gDextromethorphan Suspension Purified Water 10 g Polysorbate 80surfactant 0.22 g Uncoated Dextromethorphan Resin Complex 2.68 g CoatedDextromethorphan Resin Complex 1.00 g Placebo Suspension Base 203.15 gPurified Water QS 200 mL

Placebo Suspension Base was prepared by first dissolving 6 g of citricacid in an appropriate amount of purified water from the total 1,015 gin the main container, followed by adding 300 g of sucrose and 600 g ofhigh fructose corn syrup to achieve complete solution. In a separatecontainer, 0.03278 g of FD&C Yellow #6 was dissolved in sufficientamount of purified water and then transferred to the main container. Inanother container, 100 g of propylene glycol was added and heated to45-50° C. before additions of 3.6 g of methylparaben and 0.6 g ofpropylparaben. After both parabens were dissolved, the solution was thencooled to room temperature and 10.51 g of tragacanth gum and 3.59 g ofxanthan gum were slowly introduced to the solution to form a uniformdispersion. The gum dispersion was then transferred to the maincontainer under high speed/shear mixing condition to achieve uniformsuspension. The 2.01 g of orange flavor was added and the PlaceboSuspension Base was achieved by addition of the remaining purified waterand mixed until uniform. To prepare the final suspension, 0.22 g ofPolysorbate 80 surfactant were dissolved in 10 g of purified waterfollowed by addition of 203.15 g of Placebo Suspension Base. TheUncoated Dextromethorphan Resin complex of 2.68 g and CoatedDextromethorphan Resin Complex of 1 g were then slowly introduced to theabove dispersion under gentle mixing condition. The final suspension wasobtained by adjusting the volume to 200 mL with appropriate amount ofpurified water and mixed until uniform.

When a drug-ion-exchange resin complexes prepared according to theinvention and coated methacrylic acid copolymers such as a EUDRAGITbrand polymer coat, was mixed with a dye in the liquid suspension, thedye tended to migrate onto the surface of the polymer and resulted innon-uniform color distribution in the liquid. The use of a EUDRAGITbrand polymer in the finished liquid suspension containing water solubledyes creates issued of non-uniform color distribution due to the colormigration. Furthermore, the nature of the EUDRAGIT brand polymer, thepolymer also caused flocculation of the resin resulting in flakyagglomerates in the liquid suspension.

Example 20 Ethylcellulose-Coated Drug-Ion Exchange Resin in a LiquidSuspension Formulation—Comparative Example

Dextromethorphan suspension prepared with uncoated and AQUACOAT™ coateddextromethorphan resin complex was observed to have loose and chunkyflakes in the suspension. This was more pronounced at 40° C./75% RH thanat 25° C./60% RH.

Preparation of Coated Dextromethorphan Resin Complex

Ingredient Quantity Coated Dextromethorphan Resin Complex AQUACOATECD-30 polymer system 460.08 g Dibutyl Sebacate  33.56 g Purified Water115.97 g Dextromethorphan Resin Complex (from   600 g Example 18)

Coating solution was prepared by first gently mixing 460.08 g ofAQUACOAT ECD-30 and 33.56 g of dibutyl sebacate for 45 minutes, followedby addition of 115.97 g of purified water and continued mixing for 30minutes. The coating process was performed in Glatt GPCG-1 fluid bedprocessor by applying 615 g of the coating solution to 600 g ofDextromethorphan Resin Complex using WURSTER process that resulted in28.9% weight gain. The coated Dextromethophan Resin Complex was placedat 60° C. for 5-hour curing.

Preparation of Dextromethorphan Suspension

Ingredient Quantity Dextromethorphan ER Suspension Purified Water 10 gPolysorbate 80 surfactant 0.22 g Uncoated Dextromethorphan Resin Complex1.50 g (from Example 18) Coated Dextromethorphan Resin Complex 2.68 gPlacebo Suspension Base (from Example 18) 203.14 g Purified Water QS 200mL

To prepare the final suspension, 0.22 g of Polysorbate 80 were dissolvedin 10 g of purified water followed by addition of 203.14 g of PlaceboSuspension Base. The Uncoated Dextromethorphan Resin complex of 1.50 gand Coated Dextromethorphan Resin Complex of 2.68 g were then slowlyintroduced to the above dispersion under gentle mixing condition. Thefinal suspension was obtained by adjusting the volume to 200 mL withappropriate amount of purified water and mixed until uniform.

When the ethylcellulose-coated particles were made into a liquidsuspension, the coated particles showed as flaky, swollen and chunky, anindication of loose adhesion of the ethylcellulose coating to theparticle surface. These ethylcellulose-coated particles exhibited inlittle or no significant reductions in the release rate of the drug.

Abuse Resistant Characteristics of Products of Invention Example 21Preparation of Uncoated and Coated Dextromethorphan Resin Complex

Ingredient Quantity Uncoated Dextromethorphan Resin ComplexDextromethorphan HBr USP 95.42 g Purified Water 0.8 L AMBERLITE IRP-69resin (anhydrous) 175.82 g

The Uncoated Dextromethorphan Resin Complex was prepared by firstdissolving 95.42 g of dextromethorphan HBr in 0.8 L of purified waterheated to 75-80° C., followed by the addition of 175.82 g AMBERLITEIRP-69 resin (anhydrous) under gentle mixing for 4 hours. At thecompletion, the suspension was allowed to settle, decanted and rinsedwith purified water twice and dried in an oven maintained at 50° C.until moisture is around 5%. The dried resin complex was hand sievedthrough a 40 mesh screen.

Ingredient Quantity Dextromethorphan Resin Complex Dextromethorphan HBrUSP 954 g Purified Water 8 L AMBERLITE IRP-69 resin (anhydrous) 1,758 gKOLLIDON K-30 polyvinylpyrrolidone 116 g Purified Water 1,151 g CoatedDextromethorphan Resin Complex KOLLICOAT SR-30D polymer system 761 gTriacetin 11.4 g Purified Water 427 g Dextromethophan Resin Complex1,200 g

The Dextromethorphan Resin Complex was prepared by first dissolving 954g of dextromethorphan HBr in 8 L of purified water heated to 75-80° C.,followed by the addition of 1,758 g of AMBERLITE IRP-69 resin undergentle mixing for 4 hours. At the completion, the suspension was allowedto settle, decanted and rinsed with purified water twice and dried in anoven maintained at 50° C. until moisture is around 5%. The polyvinylpyrrolidone (PVP) solution was prepared by dissolving 116 g of KOLLIDONK-30 PVP in 1,151 g of purified water and the solution was slowly addedto the Dextromethorphan Resin Complex in a Hobart type mixer (KitchenAid) to form a uniform mass and dried at 50° C. until moisture isbetween 3-7%. The dried granules were then milled through a 40 meshscreen using CO-MIL brand mill.

Coating solution was prepared by first gently mixing 761 g of KOLLICOATSR-30D polymer system, 11.4 g of triacetin and 427 g of purified waterfor 1 hour. The coating process was performed in VECTOR™ FLM-1 fluid bedprocessor by applying 1050 g of the coating solution to 600 g ofDextromethorphan Resin Complex using Wurster process that resulted in35% weight gain. The coating conditions were controlled at am inlettemperature of 59-75° C., product temperature of 27-35° C., air flow of15-20 cfm, nozzle pressure of 2.5 kg/cm², accelerator air pressure of1.0 kg/cm² and spray rate of 4-6 g/min so that uniform coating wasachieved. The Coated Dextromethorphan Resin Complex was then placed at60° C. for 5 hours for curing.

Preparation Dextromethorphan ER Suspension

Ingredient Quantity Dextromethorphan ER Suspension Purified Water 20 gPolysorbate 80 0.11 g Uncoated Dextromethorphan Resin Complex 0.476 gCoated Dextromethorphan Resin Complex 1.596 g Sodium Metabisulfite 0.1 gPlacebo Suspension Base (from Example 18) 87.12 g Purified Water QS 100mL

To prepare the Dextromethorphan ER Suspension, the resin blend wasprepared by mixing 0.476 g of uncoated dextromethorphan resin and 1.596g of coated dextromethorphan resin. The blend was subsequently passedthrough CO-MIL™ brand mill equipped with 40 mesh screen.Dextromethorphan Suspension was prepared by dissolving 0.11 g ofPolysorbate 80 surfactant and 0.1 g of sodium metabisulfite in 20 g ofpurified water followed by addition of 87.12 g of placebo suspensionbase. The resin blend of uncoated and coated Dextromethorphan ResinComplex was then slowly introduced to the above dispersion under gentlemixing condition. The final suspension was obtained by adjusting thevolume to 100 mL with appropriate amount of purified water and mixeduntil uniform.

Another suspension was prepared with the same ingredients and procedureswith the exception that the resin blend was not milled through CO-MIL™brand mill.

Dissolution of both suspensions in 500 mL 0.1N HCl for 1 hour followedby 900 mL of pH 6.8 buffer until 24 hours under paddle, 50 rpm werecompared and results indicated no statistically significant differences.The strong external milling forces applied to the uncoated and coatedresin complex did not change the dissolution behavior of its suspensionwhen compared to the suspension prepared with un-milled resin blend,indicating that the flexible film is not disrupted.

The drug resin complex coated with polymer film showed enhancedresistance to abuse potential. The coated particles subjected togrinding mechanical forces as described above did not change itsdissolution behaviors indicating that the combined complexation andhighly flexible film make it extremely difficult to remove the drug fromthe coated particles with ordinary mechanical means.

Example 22 Preparation of Pseudoephedrine Suspension

Ingredient Quantity Placebo Suspension Base Citric Acid 8 g FD&C Yellow#6 0.064 g FD&C Red #40 0.144 g Strawberry/Banana Flavor 44.88 g HighFructose Corn Syrup 42 1,200 g Methylparaben 7.2 g Propylparaben 0.8 gGlycerin 400 g Sucrose 600 g Starch 100.26 g Xanthan Gum 8.7 g PurifiedWater QS 3484.91 g Pseudoephedrine ER Suspension Purified Water 20 gPolysorbate 80 surfactant 0.11 g Coated Pseudoephedrine Resin Complex3.11 g (from Example 8) Placebo Suspension Base 87.12 g Purified WaterQS 100 mL

Placebo Suspension Base was prepared by first dissolving 8 g of citricacid in an appropriate amount of purified water, followed by adding 600g of sucrose and 1200 g of high fructose corn syrup to achieve completesolution. In a separate container, 0.064 g of FD&C Yellow #6 and 0.144 gof FD&C Red #40 were dissolved in a sufficient amount of purified waterand then transferred to the main container. The starch (100.26 g) wasthen slowly introduced to the main container under high shear mixingcondition to achieve uniform dispersion. In another container, 400 g ofglycerin was added and heated to 45-50° C. before additions of 7.2 g ofmethylparaben and 0.8 g of propylparaben. After both parabens weredissolved, the solution was then cooled to room temperature and 8.7 g ofxanthan gum were slowly introduced to the solution to form a uniformdispersion. The gum dispersion was then transferred to the maincontainer under high speed/shear mixing condition to achieve uniformsuspension. The 44.88 g of strawberry/banana flavor was added and thePlacebo Suspension Base was achieved by addition of the remainingpurified water and mixed until uniform.

To prepare the Pseudoephedrine ER Suspension, the Coated PseudoephedrineResin Complex of 3.11 g was passed through CO-MIL™ equipped with a 40mesh screen. Pseudoephedrine Suspension was prepared by dissolving 0.11g of Polysorbate 80 surfactant in 20 g of purified water followed byaddition of 87.12 g of Placebo Suspension base. The CoatedPseudoephedrine Resin Complex was then slowly introduced to the abovedispersion under gentle mixing condition. The final suspension wasobtained by adjusting the volume to 100 mL with appropriate amount ofpurified water and mixed until uniform.

Another suspension was prepared with the same ingredients and procedureswith the exception that the Coated Pseudoephedrine Resin Complex was notmilled through CO-MIL™.

Dissolution of both suspensions in 500 mL 0.1N HCl for 1 hour followedby 900 mL of pH 6.8 buffer until 24 hours under paddle, 50 rpm werecompared and results indicated no significant differences. The strongexternal milling forces applied to the milled coated resin complex didnot change the dissolution behavior of its suspension when compared tothe suspension prepared with un-milled coated resin.

All patents, patent publications, and other publications listed in thisspecification, as well as priority documents U.S. patent applicationSer. No. 15/706,234, field Sep. 15, 2017, which is a continuation ofU.S. patent application Ser. No. 15/619,637, which is a continuation ofU.S. patent application Ser. No. 15/200,786, filed Oct. 27, 2016, whichis a continuation of U.S. patent application Ser. No. 15/047,388, filedFeb. 18, 2016, which is a continuation of U.S. patent application Ser.No. 14/508,613, filed Oct. 7, 2014, which is a continuation of U.S.patent application Ser. No. 14/155,410, filed Jan. 15, 2014, now U.S.Pat. No. 8,883,217; U.S. patent application Ser. No. 14/065,842, filedOct. 29, 2013, now U.S. Pat. No. 8,747,902, issued Jun. 10, 2014; U.S.patent application Ser. No. 14/044,105, filed Oct. 2, 2013, now U.S.Pat. No. 8,790,700, issued Jul. 29, 2014; U.S. patent application Ser.No. 13/746,654, filed Jan. 22, 2013, now U.S. Pat. No. 8,597,684, issuedDec. 3, 2013; U.S. patent application Ser. No. 13/666,424, filed Nov. 1,2012, now U.S. Pat. No. 8,491,935, issued Jul. 23, 2013; U.S. patentapplication Ser. No. 12/722,857, filed Mar. 12, 2010, now U.S. Pat. No.8,337,890, issued Dec. 25, 2012; U.S. patent application Ser. No.11/724,966, filed Mar. 15, 2007, now U.S. Pat. No. 8,062,667, issuedNov. 22, 2011; and U.S. Provisional Patent Application No. 60/783,181,filed Mar. 16, 2006, now expired, are incorporated herein by reference.While the invention has been described with reference to a particularlypreferred embodiment, it will be appreciated that modifications can bemade without departing from the spirit of the invention. Suchmodifications are intended to fall within the scope of the appendedclaims.

1. An orally ingestible aqueous liquid suspension comprising: (A)barrier coated particulates which provide a modified release profilewhich comprise: (i) a particulate drug-cation exchange resin complexcomprising at least one drug bound to a pharmaceutically acceptablewater insoluble cation exchange resin, and further comprising a waterinsoluble polymer or copolymer, or hydrophilic polymer which forms amatrix with the drug-cation exchange resin complex, which particulatedrug-cation exchange resin complex-(water insoluble polymer or copolymeror a hydrophilic polymer) matrix is capable of passing through a number40 mesh screen, and (ii) about 25% w/w to about 50% w/w of a waterpermeable, water insoluble, non-ionic, modified release polymericdiffusion barrier coating which provides a modified release profile tothe drug in said drug-cation exchange resin complex-(water insolublepolymer or copolymer or hydrophilic polymer) matrix, wherein the weightpercentage of said modified release barrier coating is based on theweight of drug-cation exchange complex-matrix without said barriercoating, wherein said at least one drug is methylphenidate, said barriercoating having an elongation factor of about 125% to about 400% andcomprising a water insoluble polymer and about 2.5% w/w to about 20% w/wplasticizer based on the weight of the barrier coating; and (B) at leastone of (iiia) and/or (iiib): (iiia) an uncoated particulatemethylphenidate-cation exchange resin complex of a size capable ofpassing through a number 40 mesh screen, wherein said uncoatedmethylphenidate-cation exchange resin complex is methylphenidate boundto a pharmaceutically acceptable water insoluble cation exchange resinand/or (iiib) methylphenidate or a pharmaceutically acceptable saltthereof which is not complexed with an ion exchange resin; and (C) apharmaceutically acceptable aqueous suspension base, wherein saidbarrier coated drug-cation exchange resin complex-matrix as defined in(A) and said at least one additional component (B) are suspended in saidbase.
 2. The orally ingestible aqueous liquid suspension according toclaim 1, wherein the water insoluble polymer or copolymer is present toform the drug-cation exchange resin complex-matrix as defined in (A). 3.The orally ingestible aqueous liquid suspension according to claim 1,wherein the hydrophilic polymer is present to form the drug-cationexchange resin complex-matrix as defined in (A) and comprises apolyvinylpyrrolidone.
 4. The orally ingestible aqueous liquid suspensionaccording to claim 1, wherein said water permeable, water insoluble,non-ionic polymeric diffusion barrier coating comprises about 30% toabout 45% by weight of the drug-cation exchange resin complex.
 5. Theorally ingestible aqueous liquid suspension according to claim 1, whichcomprises at least said uncoated particulate methylphenidate-cationexchange resin as defined in (B)(iiia).
 6. The orally ingestible aqueousliquid suspension according to claim 5, which comprises saidmethylphenidate or pharmaceutically acceptable salt thereof which is notcomplexed with an ion exchange resin as defined in (B)(iiib).
 7. Theorally ingestible aqueous liquid suspension according to claim 1 whereinsaid plasticizer comprises about 5% w/w to about 20% w/w of the coating.8. The orally ingestible aqueous liquid suspension according to claim 1,wherein said cation exchange resin used to form the complex as definedin (A) and/or B(iiia) is a sulfonated copolymer comprising styrene and adivinylbenzene.
 9. An orally ingestible aqueous liquid suspensioncomprising: (A) barrier coated particulates which provide a modifiedrelease profile for methylphenidate, which barrier coated particulatescomprise: (i) a particulate drug-cation exchange resin complexcomprising at least one drug bound to a pharmaceutically acceptablewater insoluble cation exchange resin, and a water insoluble polymer orcopolymer, or a hydrophilic polymer which forms a matrix with thedrug-cation exchange resin complex, wherein the particulate drug-cationexchange resin complex-matrix is capable of passing through a number 40mesh screen, and (ii) about 25% w/w to about 50% w/w of a waterpermeable, water insoluble, non-ionic, modified release barrier coatingwhich provides a modified release profile to the drug in saiddrug-cation exchange resin complex-(water insoluble polymer or copolymeror hydrophilic polymer) matrix, wherein the weight percentage of saidmodified release barrier coating is based on the weight of drug-cationexchange complex-matrix without said modified release barrier coating,wherein said at least one drug is methylphenidate, said modified releasebarrier coating having an elongation factor of about 125% to about 400%and comprising a water insoluble polymer and a plasticizer in an amountof about 2% w/w to about 20% w/w of the barrier coating; and (B) one ormore of (iiia) and/or (iiib): (iiia) an uncoated particulatemethylphenidate-cation exchange resin complex of a size capable ofpassing through a number 40 mesh screen, wherein said uncoatedmethylphenidate-cation exchange resin complex is methylphenidate boundto a pharmaceutically acceptable water insoluble cation exchange resinand/or (iiib) methylphenidate or a pharmaceutically acceptable saltthereof which is not complexed with an ion exchange resin; and (C) apharmaceutically acceptable aqueous suspension base, wherein saidbarrier coated drug-cation exchange resin complex-matrix as defined in(A) and said at least one additional component (B) are suspended in saidbase.
 10. The orally ingestible aqueous liquid suspension according toclaim 9, wherein the matrix comprises the hydrophilic polymer.
 11. Theorally ingestible aqueous liquid suspension according to claim 10,wherein the hydrophilic polymer comprises polyvinylpyrrolidone.
 12. Theorally ingestible aqueous liquid suspension according to claim 9.wherein said water permeable, water insoluble, non ionic polymericdiffusion barrier coating comprises about 30% to about 45% by weight ofthe drug-cation exchange resin complex.
 13. The orally ingestibleaqueous liquid suspension according to claim 9, which comprises at leastsaid uncoated particulate methylphenidate-cation exchange resin asdefined in (B)(iiia).
 14. The orally ingestible aqueous liquidsuspension according to claim 13, which comprises said methylphenidateor pharmaceutically acceptable salt thereof which is not complexed withan ion exchange resin as defined in (B)(iiib).
 15. The orally ingestibleaqueous liquid suspension according to claim 14, wherein said cationexchange resin used to form the complex as defined in (A) and/or B(iiia)is a sulfonated copolymer comprising styrene and a divinylbenzene.